Materials and methods relating to lipid metabolism

ABSTRACT

The present invention provides novel nucleic acids encoding human apolipoproteins, lipases, and lipoprotein receptor proteins; the novel polypeptides encoded by these nucleic acids; and uses of these and related products.

[0001] This application claims priority of U.S. provisional application No. 60/197,137 filed Apr. 14, 2000, and is a continuation-in-part of U.S. applications Ser. Nos. 09/714,936 filed Nov. 17, 2000, 09/714,936 filed Nov. 17, 2000, 09/667,298 filed Sept. 22, 2000, 09/631,451 filed Aug. 3, 2000, and 09/598,042 filed Jun. 20 2000, the disclosures of all of which are incorporated by reference herein in their entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to novel polynucleotides encoding proteins CG122, CG179, CG95, CG121, CG162, CG27, CG153, and CG168, which are related to proteins involved in lipid metabolism and cardiovascular disease, along with therapeutic, diagnostic and research utilities for these and related products.

BACKGROUND

[0003] Lipoproteins are globular complexes made up of cholesteryl esters and/or triglycerides enveloped by amphiphilic phospholipids and apolipoproteins, that circulate in the bloodstream. The primary function of these molecules is to serve as carriers in the transport of nonpolar lipids. Lipoproteins are grouped into several classes based on their physical characteristics, and their associated lipids and apolipoprotein(s). The major classes include chylomicrons, chylomicron remnants, very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low density lipoprotein (LDL), and high density lipoprotein (HDL). Chylomicrons contain apo AI, AII, CI, CII, CIII and E whereas chylomicron remnants are enriched for the B48 form of apo B, and apo E. VLDL contains the B100 form of apo B, apo CI, CII, CIII and E; IDL contains apo B100, CIII and E; LDL contains apo B100; and HDL contains apo AI and AII. Each of these major classes of lipoproteins also have sub-classes that contain different ratios of the primary apolipoproteins, and possibly other minor apolipoproteins. The primary function of chylomicrons and chylomicron remnants is to carry exogenous triglycerides and cholesteryl esters, whereas VLDL, IDL, LDL, and HDL, which differ in the ratio of component triglycerides and cholesteryl esters, transport endogenous fats [Chappell et al. (1998) Prog lipid Res 37:393-422; Beiseigel (1998) Eur Heart J 19 Suppl.:A20-A23; Breslow (1993) Circ 87 Suppl. III:III-16-III-21].

[0004] Dietary fat enters circulation by incorporation into chylomicrons within the epithelial cells of the intestinal walls. The exogenous fat is then transported to skeletal and adipose tissue where the chylomicrons attach themselves to the capillary walls. Here, hydrolysis of chylomicrons into chylomicron remnants, mediated by lipoprotein lipase (LPL) or hepatic lipase (HL), releases fatty acids that are taken up by neighboring endothelial cells. Chylomicron remnants are removed from circulation, by internalization into the liver, through binding to the LDL receptor or LDL-receptor-related protein (also known as the a2-macroglobulin (LRP)). Binding of chylomicron remnants to the lipoprotein receptors is mediated by their associated apolipoproteins [Chappell et al. (1998) Prog Lipid Res 37:393-422; Beiseigel (1998) Eur Heart J 19 Suppl.:A20-A23; Breslow (1993) Circ 87 Suppl. III:III-16-III-21].

[0005] Endogenous triglycerides are synthesized in the liver and secreted into the plasma by incorporation into VLDL. VLDL is circulated to tissue capillaries where LPL and HL hydrolyze VLDL into VLDL remnants. VLDL remnants are cleared from the plasma by binding to LDL receptors and LRP in the liver via binding of apoE. However, most VLDL remnants undergo successive hydrolysis of their triglycerides, mediated by LPL and HL, into IDL and LDL such that the lipid portion of LDL is composed primarily of the remaining cholesteryl esters. LDL transports cholesteryl esters to a variety of cells including adrenal cortical cells, renal cells, hepatic cells, and lymphocytes. LDL is taken up by cells through binding to the LDL receptor and LRP via receptor-mediated endocytosis [Chappell et al. (1998) Prog lipid Res 37:393-422; Beiseigel (1998) Eur Heart J 19 Suppl.:A20-A23; Breslow (1993) Circ 87 Suppl. III:III-16-16-III-21]. Within these cells, the cholesteryl esters are delivered to the lysosome, where it is hydrolyzed into cholesterol by lysosomal acid lipase (LAL). In non-hepatic cells, cholesterol is used for membrane synthesis, hormone synthesis, and also in down-regulating LDL receptor synthesis. In the liver, cholesterol is either secreted into the bile or used to synthesize bile acids [Du et al. (1998) Mol Gen Meta 64:126-134].

[0006] HDL clears free cholesterol deposited, for example, as a by product of membrane turnover and/or cell death. In addition, HDL particles are primarily responsible for reverse cholesterol transport (RCT). RCT is a process in which excess cellular cholesterol is transported from peripheral tissues to the liver where it can be processed for excretion. The efflux of excess free cholesterol from peripheral cells is mediated primarily through the ATP-binding cassette transporter 1 (ABC1), also known as the cholesterol efflux regulatory protein (CERP) [Brooks-Wilson et al. (1999) Nat Genet 22:336-345]. The cholesterol is then taken up by Apo AI into HDL. Cholesterol carried by HDL is converted by lecithin-cholesterol acyltransferase (LCAT) into cholesteryl esters, which are then exchanged for triglycerides, present on VLDL and chylomicrons, by cholesteryl ester transfer protein (CETP) [Phillips et al. (1998) Atherosclerosis 137 Suppl:S13-S17; Stein et al. (1999) Atherosclerosis 44:285-301]. VLDL is then converted into cholesterol-rich LDL as discussed above. Thus, cholesterol is transported from extrahepatic cells to LDL via HDL, and LDL delivers cholesterol back to the liver. HDL is also taken up by the liver directly via component Apo E, and the LDL receptor and LRP mechanism described above [Beiseigel (1998) Eur Heart J Suppl A: A20-A23; Breslow (1993) Circ 87 suppl III:III-16-III-21; Chappell et al. (1998) Prog Lipid Res 37:393-422].

[0007] Lipoprotein composition and transport is regulated by apolipoproteins which serve as co-factors to enzymes involved in modifying lipoproteins, or as ligand recognition moieties for lipoprotein receptors. For example, apo CII acts as the co-factor for LPL, apo F regulates the activity of CETP, and apo E is important in receptor-mediated uptake of lipoproteins due to its high affinity for the LDL receptor and LRP [Chappell et al. (1998) Prog Lipid Res 37:393-422; Wang et al. (1999) J Biol Chem 274:1814-1820]. Lipid metabolism is also regulated by lipoprotein-processing proteins which include LPL, HL, LCAT, and CETP; and lipoprotein receptors such as LDL receptor, LRP, chylomicron remnant receptor, and scavenger receptors [Breslow (1993) Circ 87 suppl III:III-16-III-21; Hiltunen et al. (1998) Atherosclerosis S81-S88].

[0008] Abnormalities in lipid metabolism increase susceptibility to atherosclerosis and cardiovascular disease. Atherogenesis begins with lipid accumulation in the intima of the arterial wall due to retention of lipoproteins, such as LDL, by matrix proteoglycans. The phospholipids associated with LDL are hydrolzed by type II secretory non-pancreatic phospholipase A2 (snpPLA₂) into free fatty acids (FFA) and lysophospholipids, both of which promote tissue inflammation [Hurt-Camejo et al. (1997) Atherosclerosis 132:1-8]. Cells present in the atherosclerotic lesions become activated leading to the production of inflammatory cytokines, snpPLA₂, LPL, macrophage colony stimulating factor (MCSF) and apo E, among others. These events result in changes in lipoprotein metabolism and the recruitment of macrophages to these sites. Both smooth muscle cells (SMC) and macrophages become lipid-filled cells, characteristic of atherosclerotic lesions, resulting from increased receptor-mediated uptake of modified LDL [Beiseigel (1998) Eur Heart J Suppl A: A20-A23; Hiltunen et a. (1998) Atherosclerosis S81-S88]. The signaling processes involved in a number of the processes described above involve receptor-activated cytosolic phospholipase C-β and A₂ [de Jonge et al. (1996) Mol Cell Biochem 157:199-210]. The resultant arterial plaques can become covered by fibrin clots and eventually occlude blood flow. Additionally, arterial plaques can rupture and break off the arterial wall. This can cause acute thrombotic events either at the site of rupture or as the circulating fragments block smaller vessels, and can lead to acute myocardial infarction, stroke, etc.

SUMMARY OF THE INVENTION

[0009] The compositions of the present invention include novel isolated polypeptides, in particular, novel human apolipoprotein, lipase, and lipoprotein receptor proteins and active variants thereof; isolated polynucleotides encoding such polypeptides, including recombinant DNA molecules, cloned genes; or degenerate variants thereof, especially naturally occurring variants such as allelic variants, antisense polynucleotide molecules, and antibodies that specifically recognize one or more epitopes present on such polypeptides, as well as hybridomas producing such antibodies.

[0010] The compositions of the present invention additionally include vectors, including expression vectors, containing the polynucleotides of the invention; cells genetically engineered to contain such polynucleotides; and cells genetically engineered to express such polynucleotides.

[0011] A nucleotide sequence encoding a protein designated CG122 (or C868) is set forth in SEQ ID NO: 1, and its deduced amino acid sequence is set forth in SEQ ID NO: 2. A nucleotide sequence encoding a protein designated CG179 (or C355) is set forth in SEQ ID NO: 3, and its deduced amino acid sequence is set forth in SEQ ID NO: 4. An extended version of SEQ ID NO: 3 is set forth in SEQ ID NO: 16 and the deduced amino acid sequence is set forth in SEQ ID NO: 17. All of these proteins are believed to be new members of the apolipoprotein family. The polypeptide set out in SEQ ID NO: 2 is 366 amino acids in length, and amino acids 1-23 represent the putative signal peptide. eMatrix search results for SEQ ID NO: 2 showed an apolipoprotein plasma lipid transport domain (6.600e-14) at amino acids 75-130 and an apolipoprotein E precursor domain (4.779e-09) at amino acids 92-142; Pfam analysis showed an Apolipoprotein A1/A4/E family domain (1.6e-06) at amino acids 4 to 251. The polypeptides set out in SEQ ID NOS: 4 or 17 are 322 amino acids and 348 amino acids in length, respectively. eMatrix search results showed a phospholipase C signature (1.439e-20) at amino acids 295-314, an ICaBP type calcium binding protein signature (4.971e-09) at amino acids 135-172, and a Cyclin protein signature (5.114e-09) at amino acids 220-254 of SEQ ID NO: 17. CG122 shows 30% identity and 53% similarity at the amino acid level to pig apolipoprotein A-IV precursor protein (Genbank Accession No. AJ222966), 28% identity and 49% similarity to apolipoprotein A-IV precursor protein from macaque (Genbank Accession No. X68361), and 27% identity and 48% similarity to chick apolipoprotein A-IV (Genbank Accession No. Y16534). CG122 shows 100% identity at the amino acid level to a sequence of GENBANK Accession No. gi12406730 and a sequence from Int'l Publication No. WO20/037491. CG179 shows 59% identity and 76% similarity at the amino acid level to human TNF-inducible protein (Genbank Accession No. AF070675), 40% identity and 59% similarity to human protein dJ6802.1 (Genbank Accession No.Z82215), and 39% identity and 58% similarity to human apolipoprotein L precursor (Genbank Accession No. AF019225). FIG. 1 shows an alignment of CG179 (C355) SEQ ID NOS: 4, 17, a sequence of GENBANK Accession No. gi12408272, and a sequence from PCT Publication No. WO99/31236, and shows that amino acids 1-93 of SEQ ID NO: 4 or 17 are missing from that published sequence. Thus, a preferred CG179 polypeptide comprises one or more (or preferably 10 or more) of amino acids 1-93 of SEQ ID NO: 4 or 17. Additional family members can be identified using either SEQ ID NO: 1 or SEQ ID NO: 3 or fragments thereof as a molecular probe.

[0012] A nucleotide sequence encoding a lipase protein designated CG95 (or C870) is set forth in SEQ ID NO: 5, and its deduced amino acid sequence is set forth in SEQ ID NO: 6. Analysis of the amino acid sequence reveals possible proteolytic cleavage sites at either amino acid residue 21 or 24 of SEQ ID NO: 6. As a result, either amino acids 1-24 or more likely amino acids 1-21 are predicted to be a signal peptide. Therefore, either amino acids 22-145 or amino acids 25-145 comprise a secreted, mature protein with lipase function. eMatrix search results on SEQ ID NO: 6 showed phospholipase A2 signatures at amino acids 44-72, 56-75, 37-56, 104-121, 104-120, 79-98; Pfam search results showed phospholipase A2 domains (1.1e-47) at amino acids 21 to 145. A nucleotide sequence encoding a lipase protein designated CG121 (or C592) is set forth in SEQ ID NO: 7, and its deduced amino acid sequence is set forth in SEQ ID NO: 8. A slightly different and shorter version of SEQ ID NO: 7 is set forth in SEQ ID NO: 18 and the deduced amino acid sequence is set forth in SEQ ID NO: 19. A nucleotide sequence encoding a lipase protein designated CG162 (or C59) is set forth in SEQ ID NO: 9. One of skill in the art could determine the corresponding amino acid sequence using techniques well known in the art to translate and analyze all possible six frames. The present invention contemplates proteins encoded by each of the six possible reading frames, in particular those proteins, polypeptides or fragments thereof exhibiting homology to lysosomal acid lipases are preferred. An extended version of SEQ ID NO: 9 is set forth in SEQ ID NO: 20 and the deduced amino acid sequence is set forth in SEQ ID NO: 21. CG95 and CG121 are believed to be new members of the phospholipase family. CG162 is believed to be a novel lysosomal acid lipase. The polypeptide set out in SEQ ID NO: 6 is 145 amino acids in length. The polypeptides set out in SEQ ID NOS: 8 or 19 are 567 amino acids or 340 amino acids in length, respectively. Pfam analysis of SEQ ID NO: 19 showed a Phosphatidylinositol-specific phospholipase domain (5.6e-16) at amino acids 291 to 326 and a PH domain (phospholipid binding) (1.8e-11) at amino acids 17 to 124; an alpha/beta hydrolase fold (8.9e-13) was also predicted at amino acids 111 to 390. The polypeptide set out in SEQ ID NO: 21 is 409 amino acids in length, and amino acids 1- 19 represent the putative signal peptide. The polypeptides of SEQ ID NO: 6 and SEQ ID NO: 8 display amino acid homology with the human PLA₂ and PLC respectively. CG95 shows 47% identity and 63% similarity at the amino acid level to rat phospholipase A2 (Genbank Accession Nos. X51529 and M37127), 47% identity and 63% similarity to rat phospholipase A2 membrane associated precursor (Genbank Accession No. D00523), and 47% identity and 63% similarity to human synovial phospholipase A2 (Genbank Accession Nos. M22431 and M22430). CG95 shows nearly 100% identity at the amino acid level to a sequence of GENBANK Accession No. gi5771420 and a sequence from Int'l Publication No. WO 20/024911. CG121 shows 73% identity and 82% similarity at the amino acid level to bovine 1 -phosphotidylinositol-4,5-bisphosphate phosphodiesterase delta-2 (Genbank Accession No. S14113), 65% identity and 76% similarity to rat phospholipase C delta-4 (Genbank Accession No. U16655), and 65% identity and 76% similarity to rat phospholipase C delta-4 (Genbank Accession No. D50455). FIG. 2 shows an alignment of CG121 (C592) SEQ ID NOS: 8, 19, a sequence of GENBANK Accession No. gi1304189, and a sequence from GENBANK Accession No. gi571466, and shows that amino acids 326-340 of SEQ ID NO: 8 or 19 are missing from that published sequence. Thus, a preferred CG179 polypeptide comprises one or more (or preferably 10 or more) of amino acids 326-340 of SEQ ID NO: 8 or 19. Additional family members can be identified using either SEQ ID NO: 5 or SEQ ID NO: 7 as a molecular probe. CG162 shows 60% identity and 75% similarity at the amino acid level to human lysosomal acid lipase (Genbank Accession No. U04285), 60% identity and 75% similarity to human lysosomal acid lipase (Genbank Accession No. U08464), and 63% identity and 78% similarity to human lysosomal acid lipase precursor (Genbank Accession No. M74775). FIG. 3 shows an alignment of SEQ ID NO: 21, a sequence from GENBANK Accession No. gi434306, and a sequence from Int'l Publication No. WO 86/03778 and shows that SEQ ID NO: 21 exhibits about 60% and 52% identity to these proteins, identified putatively as a sterol esterase and pregastric lipase, respectively. Additional family members can be identified using SEQ ID NO: 9 as a molecular probe.

[0013] A nucleotide sequence encoding a receptor protein designated CG27 (or C869) is set forth in SEQ ID NO: 10, and its deduced amino acid sequence is set forth in SEQ ID NO: 11. Four additional variant nucleotide sequences are set forth in SEQ ID NOS: 22, 24, 26 and 44 and their respective deduced amino acid sequences are set forth in SEQ ID NOS: 23, 25, 27 and 45. A nucleotide sequence encoding a receptor protein designated CG153 (or C593) is set forth in SEQ ID NO: 12, and its deduced amino acid sequence is set forth in SEQ ID NO: 13. Two additional variant nucleotide sequences are set forth in SEQ ID NOS: 28 and 30, and their respective deduced amino acid sequences are set forth in SEQ ID NOS: 29 and 31. A nucleotide sequence encoding a receptor protein designated CG168 (or C595) is set forth in SEQ ID NO: 14, and its deduced amino acid sequence is set forth in SEQ ID NO: 15. SEQ ID NO: 14 contains two possible start codons, one at nucleotide position 149 and a second possible start codon at nucleotide position 260. One of skill in the art using well known techniques, i.e., using primer extension, can determine the correct start codon. An extended version of SEQ ID NO: 14 is set forth in SEQ ID NO: 32 and the deduced amino acid sequence is set forth in SEQ ID NO: 33. The polypeptides set out in SEQ ID NOS: 11, 23, 25 or 27 are 288, 280, 314 or 247 amino acids in length, respectively. eMatrix search results showed a C-type lectin domain (2.080e-11) at amino acids 148-166 of SEQ ID NO: 23, amino acids 175-193 of SEQ ID NO: 25, and amino acids 115-133 of SEQ ID NO: 27; Pfam search results also showed a Lectin C-type domain (5.1e-05) at amino acids 163 to 257 of SEQ ID NO: 23, amino acids 190 to 284 of SEQ ID NO: 25, and amino acids 130 to 224 of SEQ ID NO: 27. The polypeptides set out in SEQ ID NO: 13, 29 or 31 are 732 amino acids, 753 amino acids or 608 amino acids in length, respectively, and amino acids 1-25 represent the putative signal peptide in all of these polypeptides. eMatrix search results for SEQ ID NO: 29 showed a Speract receptor repeat proteins domain (6.250e-27) at amino acids 311-366, a lysyl oxidase signature (1.522e-25) at amino acids 675-704 and a lysyl oxidase copper-binding region signature (5.500e-25) at amino acids 652-692, a Speract receptor repeat proteins domain (5.442e-24) at amino acids 49-104, a lysyl oxidase copper-binding region (5.671e-24) at amino acids 584-621,a lysyl oxidase signature (4.667e-20) at amino acids 589-618, a lysyl oxidase signature (4.000e-16) at amino acids 617-645, a lysyl oxidase copper-binding region (7.257e-15) at amino acids 692-733 a lysyl oxidase copper-binding region (8.327e-14) at amino acids 538-585, a lysyl oxidase copper-binding region (2.102e-13) at amino acids 620-651, a lysyl oxidase signature (5.500e-13) at amino acids 704-732, a Speract receptor repeat proteins domain (7.840e-13) at amino acids 134-145, a Speract receptor repeat proteins domain (3.972e-12) at amino acids 180-235, a speract receptor signature (5.721e-11) at amino acids 417-434, a speract receptor signature (7.000e-1 1) at amino acids 395-408, a Speract receptor repeat protein domain (8.017e-1 1) at amino acids 396-407, a speract receptor signature (9.250e-11) at amino acids 133-146, a speract receptor signature (2.469e-10) at amino acids 341-352, a lysyl oxidase signature (2.514e-10) at amino acids 533-562, a speract receptor signature (2.746e-10) at amino acids 307-324, a Speract receptor repeat proteins domain (3.526e-10) at amino acids 425-480, a speract receptor signature (4.724e-10) at amino acids 372-387, a speract receptor signature (6.311 e-10) at amino acids 64-76, and a speract receptor signature (7.429e-09) at amino acids 488-503; Pfam analysis of SEQ ID NO: 29 also showed a Lysyl oxidase domain (2.9e-173) at amino acids 529 to 732 and Scavenger receptor cysteine-rich domains (7e-82) at amino acids 51 to 145, 183 to 282, 310 to 407 and 420 to 525. Pfam analysis of SEQ ID NO: 31 showed Scavenger receptor cysteine-rich domains at amino acids 51 to 145, 165 to 262, and 275 to 380 and a lysyl oxidase domain at amino acids 384 to 587. The polypeptides set out in SEQ ID NO: 15 or 33 are 639 amino acids or 4636 amino acids in length, respectively. eMatrix and Pfam analysis of SEQ ID NO: 33 show over 100 LDL receptor signature repeats as well as numerous EGF-like domains. CG27 and CG168 are believed to be new members of the LDL receptor family. CG27 shows 31% identity and 51% similarity at the amino acid level to bovine lectin-like oxidized LDL receptor (Genbank Accession No. D89049), 29% identity and 48% similarity to human oxidized low density lipoprotein (lectin-like) receptor (Genbank Accession Nos. AB010710, AF035776, and AF079167), and 28% identity and 50% similarity to rat endothelial receptor for oxidized low density lipoprotein (Genbank Accession No. AB0005900). FIG. 4 shows an alignment of CG27 (C869) SEQ ID NOS: 11, 23, 25, 27, a sequence of GENBANK Accession No. gi7110216, and a sequence from Int'l Publication No. WO 99/13066, and shows that amino acids 111-138 of SEQ ID NO: 11 and 25, corresponding to exon 2, are missing from that published sequence. Thus, a preferred CG27 polypeptide comprises one or more (or preferably 10 or more) of amino acids 111-138 of SEQ ID NO: 11 or 25. CG168 shows 59% identity and 74% similarity at the amino acid level to chick alpha-2-macroglobulin receptor precursor (Genbank Accession No. X74904), 58% identity and 74% similarity to murine AM2 receptor (Genbank Accession No. X67469), and 58% identity and 73% similarity to human low density lipoprotein-related protein 1 (alpha-2-macroglobulin receptor) (Genbank Accession No. X13916). FIG. 5 shows an alignment of CG168 (C595) SEQ ID NOS: 15 and 33 with a sequence that maybe disclosed in Liu et al., Cancer Res. 60(7):1961-1967 (2000), and shows that amino acids 1-37 are missing from that sequence. Additional family members can be identified using SEQ ID NO: 10 or 14 as a molecular probe. CG153 shows 90% identity and 93% similarity at the amino acid level to murine lysyl oxidase-related protein 2 (Genbank Accession No. AF053368), and 54% identity and 71% similarity to human lysyl oxidase-related protein 2 (Genbank Accession No. U89942). FIG. 6 shows an alignment of CG153 (C593) SEQ ID NOS: 13, 29, 31, a sequence of GENBANK Accession No. gi3978171, and a sequence from Int'l Publication No. WO 20/0044910. Additional family members can be identified using SEQ ID NO: 12 as a molecular probe.

[0014] The polynucleotides of the invention include naturally occurring or wholly or partially synthetic DNA, e.g., cDNA and genomic DNA, and RNA, e.g., mRNA. The isolated polynucleotides of the invention include, but are not limited to, a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NOS: 2, 4, 6, 8, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43 or45; fragments thereof or the corresponding full length or mature proteins. The mature portion of each protein can be determined by expression of the corresponding cDNA in an appropriate host cell. The isolated polynucleotides of the invention further include, but are not limited to, a polynucleotide comprising the nucleotide sequence of SEQ ID NO: 1, 3, 5, 7, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42 or 44; apolynucleotide comprising the full length protein coding sequence of SEQ ID NO: 1, 3, 5, 7, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42 or 44; and a polynucleotide comprising the nucleotide sequence of the mature protein coding sequence of SEQ ID NO: 1, 3, 5, 7, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42 or 44. The polynucleotides of the present invention also include, but are not limited to, polynucleotides that encode polypeptides with biological activity, that hybridize under stringent hybridization conditions to the complement of (a) the nucleotide sequence of SEQ ID NO: 1, 3, 5, 7, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42 or 44; or (b) a nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 2, 4, 6, 8, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43 or 45; or a polynucleotide which is an allelic variant of any polynucleotide recited above; a polynucleotide which encodes a species homolog (e.g. orthologs) of any of the proteins recited above; or a polynucleotide that encodes a polypeptide comprising a specific domain or truncation of the polypeptide having an amino acid sequence of SEQ ID NO: 2, 4, 6, 8, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43or45. The polynucleotides of the invention additionally include the complement of any of the polynucleotides recited above.

[0015] The isolated polypeptides of the invention include, but are not limited to, a polypeptide comprising the amino acid sequence of SEQ ID NO: 2, 4, 6, 8, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43 or 45; fragments thereof or the corresponding full length or mature protein. Polypeptides of the invention also include polypeptides with biological activity that are encoded by (a) polynucleotides set out in SEQ ID NO: 1, 3, 5, 7, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42 or 44; or (b) polynucleotides that hybridize to the complement of the polynucleotides of (a) under stringent hybridization conditions. Biologically or immunologically active variants of the protein sequence of SEQ ID NO: 2, 4, 6, 8, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43 or 45; and “substantial equivalents” thereof (e.g., with 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% amino acid sequence identity) that preferably retain biological activity are also contemplated. The polypeptides of the invention may be wholly or partially chemically synthesized but are preferably produced by recombinant means using the genetically engineered cells (e.g. host cells) of the invention.

[0016] Protein compositions of the present invention may further comprise an acceptable carrier, such as a hydrophilic, e.g., pharmaceutically acceptable, carrier.

[0017] The invention also relates to methods for producing polypeptides of the invention comprising growing a culture of the cells of the invention in a suitable culture medium under conditions permitting expression of the desired polypeptide, and purifying the protein from the cells or the culture medium in which the cells are grown. Preferred embodiments include those in which the protein produced by such process is a mature form of the protein.

[0018] Polynucleotides according to the invention have numerous applications in a variety of techniques known to those skilled in the art of molecular biology. These techniques include use as hybridization probes, use as oligomers for PCR, use for chromosome and gene mapping, use in the recombinant production of protein, and use in generation of antisense DNA or RNA, their chemical analogs and the like. For example, when the expression of an mRNA is largely restricted to a particular cell or tissue type, polynucleotides of the invention can be used as hybridization probes to detect or quantify the presence of the particular cell or tissue mRNA in a sample using, e.g., in situ hybridization.

[0019] In other exemplary embodiments, the polynucleotides are used in diagnostics as expressed sequence tags for identifying expressed genes or, as well known in the art and exemplified by Vollrath et al., Science 258:52-59 (1992), as expressed sequence tags for physical mapping of the human genome.

[0020] The polypeptides according to the invention can be used in a variety of conventional procedures and methods that are currently applied to other proteins. For example, a polypeptide of the invention can be used to generate an antibody that specifically binds the polypeptide. Such antibodies, particularly monoclonal antibodies, are useful for detecting or quantitating the polypeptide in tissue. The polypeptides of the invention can also be used as molecular weight markers, and as a food supplement.

[0021] Methods are also provided for preventing, treating, or ameliorating a medical condition which comprises the step of administering to a mammalian subject a therapeutically effective amount of a composition comprising a protein or polypeptide of the present invention and a pharmaceutically acceptable carrier.

[0022] In particular, the polypeptides and polynucleotides of the invention may play a role in disorders involving lipid metabolism, thrombosis, and cardiovascular disease, including occlusive cardiovascular diseases such as myocardial infarction, cerebral ischemia, and angina; arterial thrombosis, such as coronary artery thrombosis and resulting myocardial infarction; cerebral artery thrombosis or intracardiac thrombosis (due to, e.g., atrial fibrillation) and resulting stroke, and other peripheral arterial thrombosis and occlusion; conditions associated with venous thrombosis, such as deep venous thrombosis and pulmonary embolism; conditions associated with exposure of the patient's blood to a foreign or injured tissue surface, including diseased heart valves, mechanical heart valves, vascular grafts, and other extracorporeal devices such as intravascular cannulas, vascular access shunts in hemodialysis patients, hemodialysis machines and cardiopulmonary bypass machines; and conditions associated with coagulapathies, such as hypercoagulability and disseminated intravascular coagulopathy.

[0023] The methods of the present invention further relate to methods for detecting the presence of the polynucleotides or polypeptides of the invention in a sample. Such methods can, for example, be utilized as part of prognostic and diagnostic evaluation of disorders as recited herein and for the identification of subjects exhibiting a predisposition to such conditions. The invention also provides kits comprising polynucleotide probes and/or monoclonal antibodies, and optionally quantitative standards, for carrying out methods of the invention. Furthermore, the invention provides methods for evaluating the efficacy of drugs, and monitoring the progress of patients, involved in clinical trials for the treatment of disorders as recited herein.

[0024] The invention also provides methods for the identification of compounds that modulate (i.e., increase or decrease) the expression or activity of the polynucleotides and/or polypeptides of the invention. Such methods can be utilized, for example, for the identification of compounds that can ameliorate symptoms of disorders as recited herein. Such methods can include, but are not limited to, assays for identifying compounds and other substances that interact with (e.g., bind to) the polypeptides of the invention.

[0025] The methods of the invention also include methods for the treatment of disorders as recited herein which may involve the administration of the polynucleotides or polypeptides of the invention to individuals exhibiting symptoms or tendencies related to disorders as recited herein. In addition, the invention encompasses methods for treating diseases or disorders as recited herein comprising the step of administering compounds and other substances that modulate the overall activity of the target CG122, CG179, CG 95, CG121, CG162, CG27, CG153, and CG168 gene products. Compounds and other substances can effect such modulation either on the level of target gene/protein expression or target protein activity.

BRIEF DESCRIPTION OF THE DRAWINGS

[0026] FIGS. 1A-1B show an alignment of CG179 (C355) SEQ ID NOS: 4, 17, a sequence of GENBANK Accession No. gi12408272, and a sequence from PCT Publication No. WO99/31236.

[0027] FIGS. 2A-2D shows an alignment of CG21(C592) SEQ ID NOS: 8, 19, a sequence of GENBANK Accession No. gi1304189, and a sequence from GENBANK Accession No. gi571466.

[0028] FIGS. 3A-3B shows an alignment of SEQ ID NO: 21, a sequence from GENBANK Accession No. gi434306, and a sequence from Int'l Publication No. WO 86/03778 and shows that SEQ ID NO: 21 exhibits about 60% and 52% identity to these proteins, identified putatively as a sterol esterase and pregastric lipase, respectively.

[0029] FIGS. 4A-4B shows an alignment of CG27 (C869) SEQ ID NOS: 11, 23, 25, 27, a sequence of GENBANK Accession No. gi7110216, and a sequence from Int'l Publication No. WO 99/13066.

[0030] FIGS. 5A-5P shows an alignment of CG168 (C595) SEQ ID NOS: 15 and 33 with a sequence that may be disclosed in Liu et al., Cancer Res. 60(7):1961-1967 (2000).

[0031] FIGS. 6A-6D shows an alignment of CG153 (C593) SEQ ID NOS: 13, 29, 31, a sequence of GENBANK Accession No. gi3978171, and a sequence from Int'l Publication No. WO 20/0044910.

DETAILED DESCRIPTION OF THE INVENTION 1. DEFINITIONS

[0032] The term “nucleotide sequence” refers to a heteropolymer of nucleotides or the sequence of these nucleotides. The terms “nucleic acid” and “polynucleotide” are also used interchangeably herein to refer to a heteropolymer of nucleotides. Generally, nucleic acid segments provided by this invention may be assembled from fragments of the genome and short oligonucleotide linkers, or from a series of oligonucleotides, or from individual nucleotides, to provide a synthetic nucleic acid which is capable of being expressed in a recombinant transcriptional unit comprising regulatory elements derived from a microbial or viral operon, or a eukaryotic gene.

[0033] The terms “oligonucleotide fragment” or a “polynucleotide fragment”, “portion,” or “segment” is a stretch of polypeptide nucleotide residues which is long enough to use in polymerase chain reaction (PCR) or various hybridization procedures to identify or amplify identical or related parts of mRNA or DNA molecules.

[0034] The terms “oligonucleotides” or “nucleic acid probes” are prepared based on the polynucleotide sequences provided in the present invention. Oligonucleotides comprise portions of such a polynucleotide sequence having at least about 15 nucleotides and usually at least about 20 nucleotides. Nucleic acid probes comprise portions of such a polynucleotide sequence having fewer nucleotides than about 6 kb, usually fewer than about 1 kb. After appropriate testing to eliminate false positives, these probes may, for example, be used to determine whether specific mRNA molecules are present in a cell or tissue or to isolate similar nucleic acid sequences from chromosomal DNA as described by Walsh et al. (Walsh, P.S. et al., 1992, PCR Methods Appl 1:241-250).

[0035] The term “probes” includes naturally occurring or recombinant or chemically synthesized single—or double—stranded nucleic acids. They may be labeled by nick translation, Klenow fill-in reaction, PCR, or other methods well known in the art. Probes of the present invention, their preparation and/or labeling are elaborated in Sambrook, J. et al., 1989, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, NY; or Ausubel, F. M. et al., 1989, Current Protocols in Molecular Biology, John Wiley & Sons, New York, N.Y., both of which are incorporated herein by reference in their entirety.

[0036] The term “stringent”′is used to refer to conditions that are commonly understood in the art as stringent. Stringent conditions can include highly stringent conditions (e.g., hybridization to filter-bound DNA in 0.5 M NaHPO_(4,) 7% sodium dodecyl sulfate (SDS), 1 mM EDTA at 65° C., and washing in 0.1X SSC/0.1% SDS at 68° C.), and moderately stringent conditions (e.g., washing in 0.2X SSC/0.1% SDS at 42° C.). Other exemplary hybridization conditions are described herein in the examples.

[0037] In instances wherein hybridization of deoxyoligonucleotides is concerned, additional exemplary stringent hybridization conditions include washing in 6X SSC/0.05% sodium pyrophosphate at 37° C. (for 14-base oligos), 48° C. (for 17-base oligos), 55° C. (for 20-base oligos), and 60° C. (for 23-base oligos).

[0038] The term “recombinant.” when used herein to refer to a polypeptide or protein, means that a polypeptide or protein is derived from recombinant (e.g., microbial, insect, or mammalian) expression systems. “Microbial” refers to recombinant polypeptides or proteins made in bacterial or fungal (e.g., yeast) expression systems. As a product, “recombinant microbial” defines a polypeptide or protein essentially free of native endogenous substances and unaccompanied by associated native glycosylation. Polypeptides or proteins expressed in most bacterial cultures, e.g., E. coli, will be free of glycosylation modifications; polypeptides or proteins expressed in yeast will have a glycosylation pattern in general different from those expressed in mammalian cells.

[0039] The term “recombinant expression vehicle or vector” refers to a plasmid or phage or virus or vector, for expressing a polypeptide from a DNA (RNA) sequence. An expression vehicle can comprise a transcriptional unit comprising an assembly of (1) a genetic element or elements having a regulatory role in gene expression, for example, promoters or enhancers, (2) a structural or coding sequence which is transcribed into mRNA and translated into protein, and (3) appropriate transcription initiation and termination sequences. Structural units intended for use in yeast or eukaryotic expression systems preferably include a leader sequence enabling extracellular secretion of translated protein by a host cell. Alternatively, where recombinant protein is expressed without a leader or transport sequence, it may include an N-terminal methionine residue. This residue may or may not be subsequently cleaved from the expressed recombinant protein to provide a final product.

[0040] The term “recombinant expression system” means host cells which have stably integrated a recombinant transcriptional unit into chromosomal DNA or carry the recombinant transcriptional unit extrachromosomally. Recombinant expression systems as defined herein will express heterologous polypeptides or proteins upon induction of the regulatory elements linked to the DNA segment or synthetic gene to be expressed. This term also means host cells which have stably integrated a recombinant genetic element or elements having a regulatory role in gene expression, for example, promoters or enhancers. Recombinant expression systems as defined herein will express polypeptides or proteins endogenous to the cell upon induction of the regulatory elements linked to the endogenous DNA segment or gene to be expressed. The cells can be prokaryotic or eukaryotic.

[0041] The term “open reading frame,” ORF, means a series of nucleotide triplets coding for amino acids without any termination codons and is a sequence translatable into protein.

[0042] The term “expression modulating fragment,” EMF, means a series of nucleotides which modulates the expression of an operably linked ORF or another EMF.

[0043] As used herein, a sequence is said to “modulate the expression of an operably linked sequence” when the expression of the sequence is altered by the presence of the EMF. EMFs include, but are not limited to, promoters, and promoter modulating sequences (inducible elements). One class of EMFs are fragments which induce the expression or an operably linked ORF in response to a specific regulatory factor or physiological event.

[0044] As used herein, an “uptake modulating fragment,” UMF, means a series of nucleotides which mediate the uptake of a linked DNA fragment into a cell. UMFs can be readily identified using known UMFs as a target sequence or target motif with the computer-based systems described below.

[0045] The presence and activity of a UMF can be confirmed by attaching the suspected UMF to a marker sequence. The resulting nucleic acid molecule is then incubated with an appropriate host under appropriate conditions and the uptake of the marker sequence is determined. As described above, a UMF will increase the frequency of uptake of a linked marker sequence.

[0046] The term “active” refers to those forms of the polypeptide which retain the biologic and/or immunologic activities of any naturally occurring polypeptide. According to the invention, the term “biologically active” with reference to the apolipoprotein-like polypeptides of the invention means that the polypeptide retains at least one of the biological activities of CG122 or CG179, preferably the apolipoprotein activity. The term “biologically active” with reference to the lipase-like polypeptides of the invention means that the polypeptide retains at least one of the biological activities of CG95, CG121, or CG162, preferably the lipase activity. The term “biologically active” with reference to the lipoprotein receptor-like polypeptides of the invention means that the polypeptide retain at least one of the biological activities of CG27, CG153, or CG168, preferably lipoprotein receptor activity. The term “immunologically active” with reference to the apolipoprotein, lipase, or lipoprotein receptor polypeptides of the invention means that the polypeptide retains at least one of the immunologic or antigenic activities of CG122, CG179, CG95, CG121, CG162, CG27, CG153 or CG168.

[0047] The term “naturally occurring polypeptide” refers to polypeptides produced by cells that have not been genetically engineered and specifically contemplates various polypeptides arising from post-translational modifications of the polypeptide including, but not limited to, acetylation, carboxylation, glycosylation, phosphorylation, lipidation and acylation.

[0048] The term “derivative” refers to polypeptides chemically modified by such techniques as ubiquitination, labeling (e.g., with radionuclides or various enzymes), pegylation (derivatization with polyethylene glycol) and insertion or substitution by chemical synthesis of amino acids such as ornithine, which do not normally occur in human proteins.

[0049] The term “variant” (or “analog” ) refers to any polypeptide differing from naturally occurring polypeptides by amino acid insertions, deletions, and substitutions, created using, for example, recombinant DNA techniques. Guidance in determining which amino acid residues may be replaced, added or deleted without abolishing activities of interest, such as apolipoprotein, lipase, or lipoprotein receptor activity, may be found by comparing the sequence of the particular polypeptide with that of homologous human or other mammalian apolipoprotein, lipase, or lipoprotein receptor polypeptides and minimizing the number of amino acid sequence changes made in regions of high homology (conserved regions) or by replacing amino acids with consensus sequence.

[0050] Preferably, amino acid “substitutions” are the result of replacing one amino acid with another amino acid having similar structural and/or chemical properties, i.e., conservative amino acid replacements. “Conservative” amino acid substitutions may be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the residues involved. For example, nonpolar (hydrophobic) amino acids include alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan, and methionine; polar neutral amino acids include glycine, serine, threonine, cysteine, tyrosine, asparagine, and glutamine; positively charged (basic) amino acids include arginine, lysine, and histidine; and negatively charged (acidic) amino acids include aspartic acid and glutamic acid. “Insertions” or “deletions” are typically in the range of about 1 to 5 amino acids. The variation allowed may be experimentally determined by systematically making insertions, deletions, or substitutions of amino acids in a polypeptide molecule using recombinant DNA techniques and assaying the resulting recombinant variants for activity.

[0051] Alternatively, where alteration of function is desired, insertions, deletions or non-conservative alterations can be engineered to produce altered polypeptides. Such alterations can, for example, alter one or more of the biological functions or biochemical characteristics of the polypeptides of the invention. For example, such alterations may change polypeptide characteristics such as ligand-binding affinities, interchain affinities, or degradation/turnover rate. Further, such alterations can be selected so as to generate polypeptides that are better suited for expression, scale up and the like in the host cells chosen for expression. For example, cysteine residues can be deleted or substituted with another amino acid residue in order to eliminate disulfide bridges.

[0052] As used herein, “substantially equivalent” can refer both to nucleotide and amino acid sequences, for example a mutant sequence, that varies from a reference sequence by one or more substitutions, deletions, or additions, the net effect of which does not result in an adverse functional dissimilarity between the reference and subject sequences. Typically, such a substantially equivalent sequence varies from one of those listed herein by no more than about 20% (i.e., the number of individual residue substitutions, additions, and/or deletions in a substantially equivalent sequence, as compared to the corresponding reference sequence, divided by the total number of residues in the substantially equivalent sequence is about 0.2 or less). Such a sequence is said to have 80% sequence identity to the listed sequence. In one embodiment, a substantially equivalent, e.g., mutant, sequence of the invention varies from a listed sequence by no more than 10% (90% sequence identity); in a variation of this embodiment, by no more than 5% (95% sequence identity); and in a further variation of this embodiment, by no more than 2% (98% sequence identity). Substantially equivalent, e.g., mutant, amino acid sequences according to the invention generally have at least 95% sequence identity with a listed amino acid sequence, whereas substantially equivalent nucleotide sequence of the invention can have lower percent sequence identities, taking into account, for example, the redundancy or degeneracy of the genetic code. For the purposes of the present invention, sequences having substantially equivalent biological activity and substantially equivalent expression characteristics are considered substantially equivalent. For the purposes of determining equivalence, truncation of the mature sequence (e.g., via a mutation which creates a spurious stop codon) should be disregarded. Sequence identity may be determined, e.g., using the Jotun Hein method.

[0053] Nucleic acid sequences encoding such substantially equivalent sequences, e.g., sequences of the recited percent identities, can routinely be isolated and identified via standard hybridization procedures well known to those of skill in the art.

[0054] Where desired, an expression vector may be designed to contain a “signal or leader sequence” which will direct the polypeptide through the membrane of a cell. Such a sequence may be naturally present on the polypeptides of the present invention or provided from heterologous protein sources by recombinant DNA techniques.

[0055] A polypeptide “fragment,” “portion,” or “segment” is a stretch of amino acid residues of at least about 5 amino acids, often at least about 7 amino acids, typically at least about 9 to 13 amino acids, and, in various embodiments, at least about 17 or more amino acids. To be active, any polypeptide must have sufficient length to display biologic and/or immunologic activity.

[0056] Alternatively, recombinant variants encoding these same or similar polypeptides may be synthesized or selected by making use of the “redundancy” in the genetic code. Various codon substitutions, such as the silent changes which produce various restriction sites, may be introduced to optimize cloning into a plasmid or viral vector or expression in a particular prokaryotic or eukaryotic system. Mutations in the polynucleotide sequence may be reflected in the polypeptide or domains of other peptides added to the polypeptide to modify the properties of any part of the polypeptide, to change characteristics such as ligand-binding affinities, interchain affinities, or degradation/turnover rate.

[0057] The term “activated” cells as used in this application are those which are engaged in extracellular or intracellular membrane trafficking, including the export of neurosecretory or enzymatic molecules as part of a normal or disease process.

[0058] The term “purified” as used herein denotes that the indicated nucleic acid or polypeptide is present in the substantial absence of other biological macromolecules, e.g., polynucleotides, proteins, and the like. In one embodiment, the polynucleotide or polypeptide is purified such that it constitutes at least 95% by weight, more preferably at least 99.8% by weight, of the indicated biological macromolecules present (but water, buffers, and other small molecules, especially molecules having a molecular weight of less than 1000 daltons, can be present).

[0059] The term “isolated” as used herein refers to a nucleic acid or polypeptide separated from at least one other component (e.g., nucleic acid or polypeptide) present with the nucleic acid or polypeptide in its natural source. In one embodiment, the nucleic acid or polypeptide is found in the presence of (if anything) only a solvent, buffer, ion, or other component normally present in a solution of the same. The terms “isolated” and “purified” do not encompass nucleic acids or polypeptides present in their natural source.

[0060] The term “infection” refers to the introduction of nucleic acids into a suitable host cell by use of a virus or viral vector.

[0061] The term “transformation” means introducing DNA into a suitable host cell so that the DNA is replicable, either as an extrachromosomal element, or by chromosomal integration.

[0062] The term “transfection” refers to the taking up of an expression vector by a suitable host cell, whether or not any coding sequences are in fact expressed.

[0063] The term “intermediate fragment” means a nucleic acid between 5 and 1000 bases in length, and preferably between 10 and 40 bp in length.

[0064] The term “secreted” includes a protein that is transported across or through a membrane, including transport as a result of signal sequences in its amino acid sequence when it is expressed in a suitable host cell. “Secreted” proteins include without limitation proteins secreted wholly (e.g., soluble proteins) or partially (e.g., receptors) from the cell in which they are expressed. “Secreted” proteins also include without limitation proteins which are transported across the membrane of the endoplasmic reticulum. “Secreted” proteins are also intended to include proteins containing non-typical signal sequences (e.g. Interleukin-1 Beta, see Krasney, P. A. and Young, P. R. (1992) Cytokine 4(2): 134 -143) and factors released from damaged cells (e.g. Interleukin-1 Receptor Antagonist, see Arend, W. P. et. al. (1998) Annu. Rev. Immunol. 16:27-55)

[0065] Each of the above terms is meant to encompasses all that is described for each, unless the context dictates otherwise.

NUCLEIC ACIDS AND POLYPEPTIDES OF THE INVENTION

[0066] Nucleotide and amino acid sequences of the invention are reported below. Fragments of the proteins of the present invention which are capable of exhibiting biological activity are also encompassed by the present invention. Fragments of the proteins may be in linear form or they may be cyclized using known methods, for example, as described in H. U. Saragovi, et al., Bio/Technology 10, 773-778 (1992) and in R. S. McDowell, et al., J. Amer. Chem. Soc. 114, 9245-9253 (1992), both of which are incorporated herein by reference. Such fragments may be fused to carrier molecules such as immunoglobulins for many purposes, including increasing the valency of protein binding sites. For example, fragments of the proteins may be fused through “linker” sequences to the Fc portion of an immunoglobulin. For a bivalent form of the protein, such a fusion could be to the Fc portion of an IgG molecule. Other immunoglobulin isotypes may also be used to generate such fusions. For example, a protein-IgM fusion would generate a decavalent form of the protein of the invention.

[0067] The present invention also provides both full-length and mature forms (for example, without a signal sequence or precursor sequence) of the disclosed proteins. The full-length form of the such proteins may be determined by translation of the nucleotide sequence of each disclosed clone. The mature form of such proteins may be obtained by expression of the disclosed full-length polynucleotide in a suitable mammalian cell or other host cell. The sequences of the mature form of the proteins are also determinable from the amino acid sequence of the full-length forms. Where proteins of the present invention are membrane bound, soluble forms of the proteins are also provided. In such forms part or all of the regions causing the proteins to be membrane bound are deleted so that the proteins are fully secreted from the cell in which it is expressed.

[0068] The present invention also provides genes corresponding to the cDNA sequences disclosed herein. The corresponding genes can be isolated in accordance with known methods using the sequence information disclosed herein. Such methods include the preparation of probes or primers from the disclosed sequence information for identification and/or amplification of genes in appropriate genomic libraries or other sources of genomic materials. Species homologs (e.g. orthologs) of the disclosed polynucleotides and proteins are also provided by the present invention. Species homologs may be isolated and identified by making suitable probes or primers from the sequences provided herein and screening a suitable nucleic acid source from the desired species. The invention also encompasses allelic variants of the disclosed polynucleotides or proteins; that is, naturally-occurring alternative forms of the isolated polynucleotide which also encode proteins which are identical, homologous or related to that encoded by the polynucleotides. The compositions of the present invention include isolated polynucleotides, including recombinant DNA molecules, cloned genes or degenerate variants thereof, especially naturally occurring variants such as allelic variants, novel isolated polypeptides, and antibodies that specifically recognize one or more epitopes present on such polypeptides. Species homologs of the disclosed polynucleotides and proteins are also provided by the present invention. Species homologs may be isolated and identified by making suitable probes or primers from the sequences provided herein and screening a suitable nucleic acid source from the desired species. The invention also encompasses allelic variants of the disclosed polynucleotides or proteins; that is, naturally-occurring alternative forms of the isolated polynucleotide which also encode proteins which are identical, homologous or related to that encoded by the polynucleotides.

2. NUCLEIC ACIDS OF THE INVENTION

[0069] The isolated polynucleotides of the invention include, but are not limited to, a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 2, 4, 6, 8, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43 or 45; or the mature protein portion thereof. A preferred nucleic acid sequence is set forth in SEQ ID NO: 1, 3, 5, 7, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42 or 44 respectively.

[0070] The isolated polynucleotides of the invention further include, but are not limited to a polynucleotide comprising the nucleotide sequence of SEQ ID NO: 1, 3, 5, 7, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42 or 44; a polynucleotide comprising the full length protein coding sequence of SEQ ID NO: 1, 3, 5, 7, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42 or 44; and apolynucleotide comprising the nucleotide sequence of the mature protein coding sequence of SEQ ID NO: 1,3,5,7,9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42 or 44. The polynucleotides of the present invention also include, but are not limited to, polynucleotides that encode polypeptides with biological activity and that hybridize under stringent hybridization conditions to the complement of either (a) the nucleotide sequence of SEQ ID NO:1, 3, 5, 7, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42 or 44; or (b) a nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 2, 4, 6, 8, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43 or45;a polynucleotide which is an allelic variant of any polynucleotide recited above; a polynucleotide which encodes a species homolog of any of the proteins recited above; or a polynucleotide that encodes a polypeptide comprising a specific domain or truncation of the polypeptide of SEQ ID NO: 2, 4, 6, 8, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41,43 or 45.

[0071] The polynucleotides of the invention additionally include the complement of any of the polynucleotides described herein.

[0072] The polynucleotides of the invention also provide polynucleotides including nucleotide sequences that are substantially equivalent to the polynucleotides recited above. Polynucleotides according to the invention can have at least about 65%, more typically at least about 70%, at least about 75%, at least about 80%, at least about 85% or at least about 90%, and even more typically at least about 95%, sequence identity to a polynucleotide recited above. The invention also provides the complement of the polynucleotides including a nucleotide sequence that has at least about 80%, more typically at least about 90%, and even more typically at least about 95%, sequence identity to a polynucleotide encoding a polypeptide recited above. The polynucleotide can be DNA (genomic, cDNA, amplified, or synthetic) or RNA. Methods and algorithms for obtaining such polynucleotides are well known to those of skill in the art and can include, for example, methods for determining hybridization conditions which can routinely isolate polynucleotides of the desired sequence identities.

[0073] A polynucleotide according to the invention can be joined to any of a variety of other nucleotide sequences by well-established recombinant DNA techniques (see Sambrook J et al. (1989) Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, NY). Useful nucleotide sequences for joining to polypeptides include an assortment of vectors, e.g., plasmids, cosmids, lambda phage derivatives, phagemids, and the like, that are well known in the art. Accordingly, the invention also provides a vector including a polynucleotide of the invention and a host cell containing the polynucleotide. In general, the vector contains an origin of replication functional in at least one organism or host cell, convenient restriction endonuclease sites, and a selectable marker for the host cell. Vectors according to the invention include expression vectors, replication vectors, probe generation vectors, and sequencing vectors. A host cell according to the invention can be a prokaryotic or eukaryotic cell and can be a unicellular organism or part of a multicellular organism.

[0074] The sequences falling within the scope of the present invention are not limited to the specific sequences herein described, but also include allelic variations thereof. Allelic variations can be routinely determined by comparing the sequence provided in SEQ ID NO: 1, 3, 5, 7, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42 or 44; or a representative fragment thereof; or a nucleotide sequence at least 99.9% identical to SEQ ID NO: 1, 3, 5, 7, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42 or 44, with a sequence from another isolate of the same species.

[0075] To accommodate codon variability, the invention includes nucleic acid molecules coding for the same amino acid sequences as do the specific ORFs disclosed herein. In other words, in the coding region of an ORF, substitution of one codon for another which encodes the same amino acid is expressly contemplated. Any specific sequence disclosed herein can be readily screened for errors by resequencing a particular fragment, such as an ORF, in both directions (i.e., sequence both strands).

[0076] The present invention further provides recombinant constructs comprising a nucleic acid having the sequence of SEQ ID NO: 1, 3, 5, 7, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42 or 44; or a fragment thereof or any other polynucleotides of the invention. In one embodiment, the recombinant constructs of the present invention comprise a vector, such as a plasmid or viral vector, into which a nucleic acid having the sequence of SEQ ID NO: 1, 3, 5, 7, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42 or 44; or a fragment thereof is inserted, in a forward or reverse orientation. In the case of a vector comprising one of the ORFs of the present invention, the vector may further comprise regulatory sequences, including for example, a promoter, operably linked to the ORF. For vectors comprising the EMFs and UMFs of the present invention, the vector may further comprise a marker sequence or heterologous ORF operably linked to the EMF or UMF. Large numbers of suitable vectors and promoters are known to those of skill in the art and are commercially available for generating the recombinant constructs of the present invention. The following vectors are provided by way of example. Bacterial: pBs, phagescript, PsiX174, pBluescript SK, pBs KS, pNH8a, pNH16a, pNH18a, pNH46a (Stratagene); pTrc99A, pKK223-3, pKK233-3, pDR540, pRIT5 (Pharmacia). Eukaryotic: pWLneo, pSV2cat, pOG44, PXTI, pSG (Stratagene) pSVK3, pBPV, pMSG, pSVL (Pharmacia).

[0077] The isolated polynucleotide of the invention may be operably linked to an expression control sequence such as the pMT2 or pED expression vectors disclosed in Kaufman et al., Nucleic Acids Res. 19, 4485-4490 (1991), in order to produce the protein recombinantly. Many suitable expression control sequences are known in the art. General methods of expressing recombinant proteins are also known and are exemplified in R. Kaufman, Methods in Enzymology 185, 537-566 (1990). As defined herein “operably linked” means that the isolated polynucleotide of the invention and an expression control sequence are situated within a vector or cell in such a way that the protein is expressed by a host cell which has been transformed (transfected) with the ligated polynucleotide/expression control sequence.

[0078] Promoter regions can be selected from any desired gene using CAT (chloramphenicol transferase) vectors or other vectors with selectable markers. Two appropriate vectors are pKK232-8 and pCM7. Particular named bacteria promoters include lac, lacZ, T3, T7, gpt, lambda P_(R), and trc. Eukaryotic promoters include CMV immediate early, HSV thymidine kinase, early and late SV40 gene promoter, LTRs from retrovirus, and mouse metallothionein-I. Selection of the appropriate vector and promoter is well within the level of ordinary skill in the art. Generally, recombinant expression vectors will include origins of replication and selectable markers permitting transformation of the host cell, e.g., the ampicillin resistance gene of E. coli and S. cerevisiae TRP 1 gene, and a promoter derived from a highly-expressed gene to direct transcription of a downstream structural sequence. Such promoters can be derived from operons encoding glycolytic enzymes such as 3-phosphoglycerate kinase (PGK), a-factor, acid phosphatase, or heat shock proteins, among others. The heterologous structural sequence is assembled in appropriate phase with translation initiation and termination sequences, and preferably, a leader sequence capable of directing secretion of translated protein into the periplasmic space or extracellular medium. Optionally, the heterologous sequence can encode a fusion protein including an N-terminal identification peptide imparting desired characteristics, e.g., stabilization or simplified purification of expressed recombinant product. Useful expression vectors for bacterial use are constructed by inserting a structural DNA sequence encoding a desired protein together with suitable translation initiation and termination signals in operable reading phase with a functional promoter. The vector will comprise one or more phenotypic selectable markers and an origin of replication to ensure maintenance of the vector and to, if desirable, provide amplification within the host. Suitable prokaryotic hosts for transformation include E. coli, Bacillus subtilis, Salmonella typhimurium and various species within the genera Pseudomonas, Streptomyces, and Staphylococcus, although others may also be employed as a matter of choice.

[0079] As a representative but non-limiting example, useful expression vectors for bacterial use can comprise a selectable marker and bacterial origin of replication derived from commercially available plasmids comprising genetic elements of the well known cloning vector pBR322 (ATCC 37017). Such commercial vectors include, for example, pKK223-3 (Pharmacia Fine Chemicals, Uppsala, Sweden) and GEM 1 (Promega Biotech, Madison, WI, USA). These pBR322 “backbone” sections are combined with an appropriate promoter and the structural sequence to be expressed. Following transformation of a suitable host strain and growth of the host strain to an appropriate cell density, the selected promoter is induced or derepressed by appropriate means (e.g., temperature shift or chemical induction) and cells are cultured for an additional period. Cells are typically harvested by centrifugation, disrupted by physical or chemical means, and the resulting crude extract retained for further purification.

[0080] Included within the scope of the nucleic acid sequences of the invention are nucleic acid sequences that hybridize under stringent conditions to a fragment of the DNA sequence of SEQ ID NO: 1, 3, 5, 7, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42 or 44; which fragment is greater than about 10 bp, preferably 20-50 bp, greater than 100 bp, greater than 300 bp, or greater than 500 bp. In accordance with the invention, polynucleotide sequences which encode the novel nucleic acids, or functional equivalents thereof, may be used to generate recombinant DNA molecules that direct the expression of that nucleic acid, or a functional equivalent thereof, in appropriate host cells.

[0081] The nucleic acid sequences of the invention are further directed to sequences which encode variants of the described nucleic acids. These amino acid sequence variants may be prepared by methods known in the art by introducing appropriate nucleotide changes into a native or variant polynucleotide. There are two variables in the construction of amino acid sequence variants: the location of the mutation and the nature of the mutation. The amino acid sequence variants of the nucleic acids are preferably constructed by mutating the polynucleotide to give an amino acid sequence that does not occur in nature. These amino acid alterations can be made at sites that differ in the nucleic acids from different species or other family members (variable positions) or in highly conserved regions (constant regions). Sites at such locations will typically be modified in series, e.g., by substituting first with conservative choices (e.g., hydrophobic amino acid to a different hydrophobic amino acid) and then with more distant choices (e.g., hydrophobic amino acid to a charged amino acid), and then deletions or insertions may be made at the target site. Amino acid sequence deletions generally range from about 1 to 30 residues, preferably about 1 to 10 residues, and are typically contiguous. Amino acid insertions include amino- and/or carboxyl-terminal fusions ranging in length from one to one hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues. Intrasequence insertions may range generally from about 1 to 10 amino residues, preferably from 1 to 5 residues. Examples of terminal insertions include the heterologous signal sequences necessary for secretion or for intracellular targeting in different host cells, and sequences such as FLAG or poly-histidine sequences useful for purifying the expressed protein..

[0082] In a preferred method, polynucleotides encoding the novel nucleic acids are changed via site-directed mutagenesis. This method uses oligonucleotide sequences that encode the polynucleotide sequence of the desired amino acid variant, as well as a sufficient adjacent nucleotide on both sides of the changed amino acid to form a stable duplex on either side of the site of being changed. In general, the techniques of site-directed mutagenesis are well known to those of skill in the art and this technique is exemplified by publications such as, Edelman et al., DNA 2:183 (1983). A versatile and efficient method for producing site-specific changes in a polynucleotide sequence was published by Zoller and Smith, Nucleic Acids Res. 10:6487-6500 (1982). PCR may also be used to create amino acid sequence variants of the novel nucleic acids. When small amounts of template DNA are used as starting material, primer(s) that differs slightly in sequence from the corresponding region in the template DNA can generate the desired amino acid variant. PCR amplification results in a population of product DNA fragments that differ from the polynucleotide template encoding the polypeptide at the position specified by the primer. The product DNA fragments replace the corresponding region in the plasmid and this gives the desired amino acid variant.

[0083] A further technique for generating amino acid variants is the cassette mutagenesis technique described in Wells et al., Gene 34:315 (1985); and other mutagenesis techniques well known in the art, such as, for example, the techniques in Sambrook et al., supra, and Current Protocols in Molecular Biology, Ausubel et al. Due to the inherent degeneracy of the genetic code, other DNA sequences which encode substantially the same or a functionally equivalent amino acid sequence may be used in the practice of the invention for the cloning and expression of these novel nucleic acids. Such DNA sequences include those which are capable of hybridizing to the appropriate novel nucleic acid sequence under stringent conditions.

3. HOSTS

[0084] The present invention further provides host cells genetically engineered to contain the polynucleotides of the invention. For example, such host cells may contain nucleic acids of the invention introduced into the host cell using known transformation, transfection or infection methods. The present invention still further provides host cells genetically engineered to express the polynucleotides of the invention, wherein such polynucleotides are in operative association with a regulatory sequence heterologous to the host cell which drives expression of the polynucleotides in the cell.

[0085] Knowledge of DNA sequences provided by the invention (e.g. DNA encoding apolipoprotein, lipase, or lipoprotein receptor polypeptides of the invention) allows for modification of cells to permit, or increase, expression of endogenous polypeptide. Cells can be modified (e.g., by homologous recombination) to provide increased polypeptide expression by replacing, in whole or in part, the naturally occurring promoter with all or part of a heterologous promoter so that the cells express the protein at higher levels. The heterologous promoter is inserted in such a manner that it is operatively linked to the desired protein encoding sequences. See, for example, PCT International Publication No.

[0086] WO 94/12650, PCT International Publication No. WO 92/20808, and PCT International Publication No. WO 91/09955. It is also contemplated that, in addition to heterologous promoter DNA, amplifiable marker DNA (e.g., ada, dhfr, and the multifunctional CAD gene which encodes carbamyl phosphate synthase, aspartate transcarbamylase, and dihydroorotase) and/or intron DNA may be inserted along with the heterologous promoter DNA. If linked to the desired protein coding sequence, amplification of the marker DNA by standard selection methods results in co-amplification of the desired protein coding sequences in the cells.

[0087] The host cell can be a higher eukaryotic host cell, such as a mammalian cell, a lower eukaryotic host cell, such as a yeast cell, or the host cell can be a prokaryotic cell, such as a bacterial cell. Introduction of the recombinant construct into the host cell can be effected by calcium phosphate transfection, DEAE dextran mediated transfection, or electroporation (Davis, L. et al., Basic Methods in Molecular Biology (1986)). The host cells containing one of the polynucleotides of the invention, can be used in conventional manners to produce the gene product encoded by the isolated fragment (in the case of an ORF) or can be used to produce a heterologous protein under the control of the EMF.

[0088] Any host/vector system can be used to express one or more of the ORFs of the present invention. These include, but are not limited to, eukaryotic hosts such as HeLa cells, Cv-1 cell, COS cells, and Sf9 cells, as well as prokaryotic host such as E. coli and B. subtilis. The most preferred cells are those which do not normally express the particular polypeptide or protein or which expresses the polypeptide or protein at low natural level. Mature proteins can be expressed in mammalian cells, yeast, bacteria, or other cells under the control of appropriate promoters. Cell-free translation systems can also be employed to produce such proteins using RNAs derived from the DNA constructs of the present invention. Appropriate cloning and expression vectors for use with prokaryotic and eukaryotic hosts are described by Sambrook, et al., in Molecular Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor, N.Y. (1989), the disclosure of which is hereby incorporated by reference.

[0089] Various mammalian cell culture systems can also be employed to express recombinant protein. Examples of mammalian expression systems include the COS-7 lines of monkey kidney fibroblasts, described by Gluzman, Cell 23:175 (1981), and other cell lines capable of expressing a compatible vector, for example, the C127, 3T3, CHO, HeLa and BHK cell lines. Mammalian expression vectors will comprise an origin of replication, a suitable promoter and also any necessary ribosome binding sites, polyadenylation site, splice donor and acceptor sites, transcriptional termination sequences, and 5′ flanking nontranscribed sequences. DNA sequences derived from the SV40 viral genome, for example, SV40 origin, early promoter, enhancer, splice, and polyadenylation sites may be used to provide the required nontranscribed genetic elements. Recombinant polypeptides and proteins produced in bacterial culture are usually isolated by initial extraction from cell pellets, followed by one or more salting-out, aqueous ion exchange or size exclusion chromatography steps. Protein refolding steps can be used, as necessary, in completing configuration of the mature protein. Finally, high performance liquid chromatography (HPLC) can be employed for final purification steps. Microbial cells employed in expression of proteins can be disrupted by any convenient method, including freeze-thaw cycling, sonication, mechanical disruption, or use of cell lysing agents.

[0090] A number of types of cells may act as suitable host cells for expression of the protein. Mammalian host cells include, for example. monkey COS cells, Chinese Hamster Ovary (CHO) cells, human kidney 293 cells, human epidermal A43 1 cells, human Colo205cells, 3T3 cells, CV-1 cells, other transformed primate cell lines, normal diploid cells, cell strains derived from in vitro culture of primary tissue, primary explants, HeLa cells, mouse L cells, BHK, HL-60, U937, HaK or Jurkat cells.

[0091] Alternatively, it may be possible to produce the protein in lower eukaryotes such as yeast, insects or in prokaryotes such as bacteria. Potentially suitable yeast strains include Saccharomyces cerevisiae, Schizosaccharomyces pombe, Kluyveromyces strains, Candida, or any yeast strain capable of expressing heterologous proteins. Potentially suitable bacterial strains include Escherichia coli, Bacillus subtilis, Salmonella typhimurium, or any bacterial strain capable of expressing heterologous proteins. If the protein is made in yeast or bacteria, it may be necessary to modify the protein produced therein, for example by phosphorylation or glycosylation of the appropriate sites, in order to obtain the functional protein. Such covalent attachments may be accomplished using known chemical or enzymatic methods.

[0092] In another embodiment of the present invention, cells and tissues may be engineered to express an endogenous gene comprising the polynucleotides of the invention under the control of inducible regulatory elements, in which case the regulatory sequences of the endogenous gene may be replaced by homologous recombination. As described herein, gene targeting can be used to replace a gene's existing regulatory region with a regulatory sequence isolated from a different gene or a novel regulatory sequence synthesized by genetic engineering methods. Such regulatory sequences may be comprised of promoters, enhancers, scaffold-attachment regions, negative regulatory elements, transcriptional initiation sites, regulatory protein binding sites or combinations of said sequences. Alternatively, sequences which affect the structure or stability of the RNA or protein produced may be replaced, removed, added, or otherwise modified by targeting, including polyadenylation signals. mRNA stability elements, splice sites, leader sequences for enhancing or modifying transport or secretion properties of the protein, or other sequences which alter or improve the function or stability of protein or RNA molecules.

[0093] The targeting event may be a simple insertion of the regulatory sequence, placing the gene under the control of the new regulatory sequence, e.g., inserting a new promoter or enhancer or both upstream of a gene. Alternatively, the targeting event may be a simple deletion of a regulatory element, such as the deletion of a tissue-specific negative regulatory element. Alternatively, the targeting event may replace an existing element; for example, a tissue-specific enhancer can be replaced by an enhancer that has broader or different cell-type specificity than the naturally occurring elements. Here, the naturally occurring sequences are deleted and new sequences are added. In all cases, the identification of the targeting event may be facilitated by the use of one or more selectable marker genes that are contiguous with the targeting DNA, allowing for the selection of cells in which the exogenous DNA has integrated into the host cell genome. The identification of the targeting event may also be facilitated by the use of one or more marker genes exhibiting the property of negative selection, such that the negatively selectable marker is linked to the exogenous DNA, but configured such that the negatively selectable marker flanks the targeting sequence, and such that a correct homologous recombination event with sequences in the host cell genome does not result in the stable integration of the negatively selectable marker. Markers useful for this purpose include the Herpes Simplex Virus thymidine kinase (TK) gene or the bacterial xanthine-guanine phosphoribosyl-transferase (gpt) gene.

[0094] Exemplary gene targeting or gene activation techniques which can be used in accordance with this aspect of the invention are more particularly described in U.S. Pat. No. 5,272,071 to Chappel; U.S. Pat. No. 5,578,461 to Sherwin et al.; International Application No. PCT/U.S.92/09627 (WO 93/09222) by Selden et al.; and International Application No. PCT/U.S.90/06436 (WO 91/06667) by Skoultchi et al., each of which is incorporated by reference herein in its entirety.

4. POLYPEPTIDES OF THE INVENTION

[0095] The isolated polypeptides of the invention include, but are not limited to, a polypeptide comprising the amino acid sequence of SEQ ID NO: 2, 4, 6, 8, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43 or 45; or the amino acid sequence encoded by the DNA of SEQ ID NO: 1, 3, 5, 7, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42 or 44; or the corresponding full length or mature protein. Polypeptides of the invention also include polypeptides preferably with biological or immunological activity that are encoded by (a) the polynucleotide of SEQ ID NO: 1, 3, 5, 7, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42 or 44; or (b) polynucleotides encoding SEQ ID NO: 2, 4, 6, 8, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35. 37, 39, 41, 43 or 45; or polynucleotides that hybridize to the complement of the polynucleotides of either (a) or (b) under stringent hybridization conditions. Biologically active or immunologically active variants of the polypeptide amino acid sequence of SEQ ID NO: 2, 4, 6, 8, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43 or 45, or the corresponding full length or mature protein; and “substantial equivalents” thereof (e.g., with 65%, 70%, 75%, 80%, 85%, 90%, typically 95%, more typically 98%, or most typically 99% amino acid identity) that retain a biological activity, preferably apoprotein, lipase, or lipoprotein receptor activity are contemplated. Polypeptides encoded by allelic variants may have a similar, increased, or decreased activity compared to polypeptides of SEQ ID NOS: 2, 4, 6, 8, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43 or45.

[0096] Protein compositions of the present invention may further comprise an acceptable carrier, such as a hydrophilic, e.g., pharmaceutically acceptable, carrier.

[0097] The invention also relates to methods for producing a polypeptide comprising growing a culture of the cells of the invention in a suitable culture medium, and purifying the protein from the cells or the culture in which the cells are grown. For example, the methods of the invention include a process for producing a polypeptide in which a host cell containing a suitable expression vector that includes a polynucleotide of the invention is cultured under conditions that allow expression of the encoded polypeptide. The polypeptide can be recovered from the cells or the culture medium, and further purified. Preferred embodiments include those in which the protein produced by such process is a full length or mature form of the protein.

[0098] The present invention further provides isolated polypeptides encoded by the nucleic acid fragments of the present invention or by degenerate variants of the nucleic acid fragments of the present invention. By “degenerate variant” is intended nucleotide fragments which differ from a nucleic acid fragment of the present invention (e.g., an ORF) by nucleotide sequence due to the degeneracy of the genetic code, but which encode an identical polypeptide sequence. Preferred nucleic acid fragments of the present invention are the ORFs that encode proteins. A variety of methodologies known in the art can be utilized to obtain any one of the isolated polypeptides or proteins of the present invention. At the simplest level, the amino acid sequence can be synthesized using commercially available peptide synthesizers. This is particularly useful in producing small peptides and fragments of larger polypeptides. Fragments are useful, for example, in generating antibodies against the native polypeptide. In an alternative method, the polypeptide or protein is purified from host cells which produce the polypeptide or protein. One skilled in the art can readily follow known methods for isolating polypeptides and proteins in order to obtain one of the isolated polypeptides or proteins of the present invention. These include, but are not limited to, immunochromatography, HPLC, size-exclusion chromatography, ion-exchange chromatography, and immuno-affinity chromatography. See, e.g., Scopes, Protein Purification: Principles and Practice, Springer-Verlag (1994); Sambrook, et al., in Molecular Cloning: A Laboratory Manual; Ausubel et al., Current Protocols in Molecular Biology. Polypeptide fragments that retain biological/immunological activity include fragments encoding greater than about 100 amino acids, or greater than about 200 amino acids, and fragments that encode specific protein domains.

[0099] The polypeptides and proteins of the present invention can alternatively be purified from cells which have been altered to express the desired polypeptide or protein. As used herein, a cell is said to be altered to express a desired polypeptide or protein when the cell, through genetic manipulation, is made to produce a polypeptide or protein which it normally does not produce or which the cell normally produces at a lower level. One skilled in the art can readily adapt procedures for introducing and expressing either recombinant or synthetic sequences into eukaryotic or prokaryotic cells in order to generate a cell which produces one of the polypeptides or proteins of the present invention. The purified polypeptides can be used in in vitro binding assays which are well known in the art to identify molecules which bind to the polypeptides.

[0100] Sources for test compounds that may be screened for ability to bind to or modulate (i.e., increase or decrease) the activity of polypeptides of the invention include (1) inorganic and organic chemical libraries, (2) natural product libraries, and (3) combinatorial libraries comprised of either random or mimetic peptides, oligonucleotides or organic molecules.

[0101] Chemical libraries may be readily synthesized or purchased from a number of commercial sources, and may include structural analogs of known compounds or compounds that are identified as “hits” or “leads” via natural product screening.

[0102] The sources of natural product libraries are microorganisms (including bacteria and fungi), animals, plants or other vegetation, or marine organisms, and libraries of mixtures for screening may be created by: (1) fermentation and extraction of broths from soil, plant or marine microorganisms or (2) extraction of the organisms themselves. Natural product libraries include polyketides, non-ribosomal peptides, and (non-naturally occurring) variants thereof. For a review, see Science 282:63-68 (1998).

[0103] Combinatorial libraries are composed of large numbers of peptides, oligonucleotides or organic compounds and can be readily prepared by traditional automated synthesis methods, PCR, cloning or proprietary synthetic methods. Of particular interest are peptide and oligonucleotide combinatorial libraries. Still other libraries of interest include peptide, protein, peptidomimetic, multiparallel synthetic collection, recombinatorial, and polypeptide libraries. For a review of combinatorial chemistry and libraries created therefrom, see Myers, Curr. Opin. Biotechnol. 8:701-707 (1997). For reviews and examples of peptidomimetic libraries, see Al-Obeidi et al., Mol. Biotechnol, 9(3):205-23 (1998); Hruby et al., Curr Opin Chem Biol, 1(1):114-19 (1997); Dorner et al., Bioorg Med Chem, 4(5):709-15 (1996) (alkylated dipeptides).

[0104] Identification of modulators through use of the various libraries described herein permits modification of the candidate “hit” (or “lead”) to optimize the capacity of the “hit” to bind a polypeptide of the invention. The molecules identified in the binding assay are then tested for antagonist or agonist activity in in vivo tissue culture or animal models that are well known in the art. In brief, the molecules are titrated into a plurality of cell cultures or animals and then tested for either cell/animal death or prolonged survival of the animal/cells.

[0105] In addition, the binding molecules may be complexed with toxins, e.g., ricin or cholera, or with other compounds that are toxic to cells such as radioisotopes. The toxin-binding molecule complex is then targeted to a tumor or other cell by the specificity of the binding molecule for a polypeptide of the invention. Alternatively, the polypeptide of the invention or binding molecules may be complexed with imaging agents for targeting and imaging purposes.

[0106] The protein of the invention may also be expressed as a product of transgenic animals, e.g., as a component of the milk of transgenic cows, goats, pigs, or sheep which are characterized by somatic or germ cells containing a nucleotide sequence encoding the protein.

[0107] The protein may also be produced by known conventional chemical synthesis. Methods for constructing the proteins of the present invention by synthetic means are known to those skilled in the art. The synthetically-constructed protein sequences, by virtue of sharing primary, secondary or tertiary structural and/or conformational characteristics with proteins may possess biological properties in common therewith, including protein activity. Thus, they may be employed as biologically active or immunological substitutes for natural, purified proteins in screening of therapeutic compounds and in immunological processes for the development of antibodies.

[0108] The proteins provided herein also include proteins characterized by amino acid sequences similar to those of purified proteins but into which modification are naturally provided or deliberately engineered. For example, modifications in the peptide or DNA sequences can be made by those skilled in the art using known techniques. Modifications of interest in the protein sequences may include the alteration, substitution, replacement, insertion or deletion of a selected amino acid residue in the coding sequence. For example, one or more of the cysteine residues may be deleted or replaced with another amino acid to alter the conformation of the molecule. Techniques for such alteration, substitution, replacement, insertion or deletion are well known to those skilled in the art (see, e.g., U.S. Pat. No. 4,518,584). Preferably, such alteration, substitution, replacement, insertion or deletion retains a desired activity of the protein.

[0109] Other fragments and derivatives of the sequences of proteins which would be expected to retain protein activity in whole or in part and may thus be useful for screening or other immunological methodologies may also be easily made by those skilled in the art given the disclosures herein. Such modifications are believed to be encompassed by the present invention.

[0110] The protein may also be produced by operably linking the isolated polynucleotide of the invention to suitable control sequences in one or more insect expression vectors, and employing an insect expression system. Materials and methods for baculovirus/insect cell expression systems are commercially available in kit form from, e.g., Invitrogen, San Diego, Calif., U.S.A. (the MaxBat.RTM. kit), and such methods are well known in the art, as described in Summers and Smith, Texas Agricultural Experiment Station Bulletin No. 1555 (1987), incorporated herein by reference. As used herein, an insect cell capable of expressing a polynucleotide of the present invention is “transformed.”

[0111] The protein of the invention may be prepared by culturing transformed host cells under culture conditions suitable to express the recombinant protein. The resulting expressed protein may then be purified from such culture (i.e., from culture medium or cell extracts) using known purification processes, such as gel filtration and ion exchange chromatography. The purification of the protein may also include an affinity column containing agents which will bind to the protein; one or more column steps over such affinity resins as concanavalin A-agarose, heparin-toyopearl™ or Cibacrom blue 3GA Sepharose™; one or more steps involving hydrophobic interaction chromatography using such resins as phenyl ether, butyl ether, or propyl ether; or immunoaffinity chromatography.

[0112] Alternatively, the protein of the invention may also be expressed in a form which will facilitate purification. For example, it may be expressed as a fusion protein, such as fused with maltose binding protein (MBP), glutathione-S-transferase (GST), thioredoxin (TRX), or as a His tag. Kits for expression and purification of such fusion proteins are commercially available from New England BioLab (Beverly, Mass.), Pharmacia (Piscataway, N.J.), Invitrogen, and Qiagen respectively. The protein can also be tagged with an epitope and subsequently purified by using a specific antibody directed to such epitope. One such epitope (“Flag“) is commercially available from Kodak (New Haven, Conn.).

[0113] Finally, one or more reverse-phase high performance liquid chromatography (RP-HPLC) steps employing hydrophobic RP-HPLC media, e.g., silica gel having pendant methyl or other aliphatic groups, can be employed to further purify the protein. Some or all of the foregoing purification steps, in various combinations, can also be employed to provide a substantially homogeneous isolated recombinant protein. The protein thus purified is substantially free of other mammalian proteins and is defined in accordance with the present invention as an “isolated protein.”

[0114] The polypeptides of the invention include CG122, CG179, CG95, CG121, CG162, CG27, CG153, and CG168 analogs (variants). This embraces fragments of CG122, CG179, CG95, CG121, CG162, CG27, CG153, and CG168; as well as analogs (variants) thereof in which one or more amino acids has been deleted, inserted, or substituted. Analogs of the invention also embrace fusions or modifications of CG122, CG179, CG95, CG121, CG162, CG27, CG153, and CG168; wherein the protein or analog is fused to another moiety or moieties, e.g., targeting moiety or another therapeutic agent. Such analogs may exhibit improved properties such as activity and/or stability. Examples of moieties which may be fused to CG122, CG179, CG95, CG121, CG162, CG27, CG153, CG168 or an analog include, for example, targeting moieties which provide for the delivery of polypeptide to desired cell types. Other moieties which may be fused to CG122, CG179, CG95, CG121, CG162, CG27, CG153, CG168 or an analog include therapeutic agents which are used for treatment of disorders described herein.

5. GENE THERAPY

[0115] Mutations in the CG122, CG179, CG95, CG121, CG162, CG27, CG153 or CG168 gene may result in loss of normal function of the encoded protein. The invention thus provides gene therapy to restore normal CG122, CG179, CG95, CG121, CG162, CG27, CG153 or CG168 activity; or to treat disease states involving CG122, CG179, CG95, CG121, CG162, CG27, CG153 or CG168. Delivery of a functional CG122, CG179, CG95, CG121, CG162, CG27, CG153 or CG168 gene to appropriate cells is effected ex vivo, in situ, or in vivo by use of vectors, and more particularly viral vectors (e.g., adenovirus, adeno-associated virus, or a retrovirus), or ex vivo by use of physical DNA transfer methods (e.g., liposomes or chemical treatments). See, for example, Anderson, Nature, supplement to vol. 392, no. 6679, pp.25-20 (1998). For additional reviews of gene therapy technology see Friedmann, Science, 244: 1275-1281 (1989); Verma, Scientific American: 68-84 (1990); and Miller, Nature, 357: 455-460 (1992). Alternatively, it is contemplated that in other human disease states, preventing the expression of or inhibiting the activity of CG122, CG179, CG95, CG121, CG162, CG27, CG153 or CG168 will be useful in treating the disease states. It is contemplated that antisense therapy or gene therapy could be applied to negatively regulate the expression of CG122, CG179, CG95, CG121, CG162, CG27, CG153 or CG168.

5.1 TRANSGENIC ANIMALS

[0116] With a polynucleotide of the invention, transgenic animals can be produced wherein a polynucleotide encoding the desired specific binding agent is introduced into the genome of a recipient animal in a manner that permits expression of the encoded specific binding agent, or alternatively, the sequence in an animal can be disabled so that at least one allele in nonfunctional. Two methods of producing transgenic mice are widely used. In one method, embryonic stem cells (ES cells) in tissue culture are transformed with a desired DNA, and in an alternative method, a desired polynucleotide is injected into the pronucleus of a fertilized mouse egg.

[0117] In the first method, ES cells are harvested from the inner cell mass of mouse blastocysts. The isolated cells can be grown in culture and generally retain their full potential to produce all the cells of the mature animal. Cells growing in culture are transformed/transfected by methods well known and routinely used in the art, and cells are selected based generally on expression of some marker encoded by the transforming DNA (see below). Selected cells are then injected into the inner cell mass (ICM) of mouse blastocyst. These embryos are transferred to the uterus of a pseudo pregnant mouse (produced by mating a female mouse with a vasectomized male). Offspring are then tested by removing a small piece of tissue from the tail and examine its DNA for the desired gene and offspring that are found to have the desired DNA will be heterozygous. A homozygous strain can then be produced by mating two heterozygotes.

[0118] In the second method freshly fertilized eggs are harvested before the sperm head becomes a pronucleus. Desired DNA is injected into the male pronucleus and when the pronuclei have fused to form the diploid zygote nucleus, the zygote is allowed to form a 2-cell embryo. These embryos are then implanted in a pseudopregnant mouse as described above and resulting offspring examined, also as described.

[0119] The design of the DNA used in these methods is based on the desired results, including, for example, restoring gene function in a mutant animal or knocking out the function of a particular locus. In either case, the designed DNA will include the targeted gene insertion, and generally neo^(r), a selectable marker gene that encodes an enzyme that inactivates the antibiotic neomycin (and its relatives) and/or tk, a gene that encodes thymidine kinase, an enzyme that phosphorylates the nucleoside analog gancyclovir. DNA polymerase fails to discriminate against the resulting nucleotide and inserts this nonfunctional nucleotide into freshly-replicating DNA which is generally lethal to the cell. Following random insertion, the entire vector, including the tk gene, is stably integrated into the host genome and the resulting cells are resistant to neomycin but killed by gancyclovir. In some cells, homologous recombination will occur wherein only part of the designed DNA will stably insert into the host genome. Cells are therefore first selected by culturing the cells in neomycin; cells that failed to take up the vector are killed. A second selection includes culturing the selected cells in gancyclovir which will identify those cells transformed by homologous recombination. These cells are then injected into the inner cell mass of mouse blastocyst as described above. Other selectable markers are well known in the art and can be utilized in place of those described herein. these methods.

[0120] When the transforming DNA is nonfunctional (for example, in the production of knockout animals to produce a “null” allele), the resulting offspring will be heterozygous. Mating of heterozygous transgenic animals, however, will produce a strain of “knockouts” homozygous for the null allele gene. In general, transgenic animals are produced using mice.

[0121] Alternatively, sheep fibroblasts growing can be grown in tissue culture and transformed or transfected DNA as described above, including, for example, a neomycin-resistance gene to aid in selection, and a desired gene sequence under control of one or more promoter sites from the beta-lactoglobulin gene. Integration of this chimeric gene permits expression in milk-producing cells. Successfully-transformed cells can be fused with enucleated sheep eggs and implanted in the uterus of a ewe. Surviving offspring are expected to produce the desired protein in milk. See, Pollock, et al., J. Immunol. Meth. 231:147-157 (1999); Little, et al., Immunol. Today 8: 364-370 (2000). The protein of the invention may also be expressed as a product of transgenic animals, and particularly as a component of the milk of transgenic cows, goats, or pigs, which are characterized by somatic or germ cells containing a nucleotide sequence encoding the protein.

[0122] In methods to determine biological functions of CG122, CG179, CG95, CG121, CG162, CG27, CG153, and CG168, in vivo, one or more genes provided by the invention are either over expressed or inactivated in the germ line of animals using homologous recombination [Capecchi, Science 244:1288-1292 (1989)]. Animals in which the gene is over expressed, under the regulatory control of exogenous or endogenous promoter elements, are known as transgenic animals. Animals in which an endogenous gene has been inactivated by homologous recombination are referred to as “knockout” animals. Knockout animals, preferably non-human mammals, can be prepared as described in U.S. Pat. No. 5,557,032, incorporated herein by reference. Such transgenic animals are useful to determine the roles CG122, CG179, CG95, CG121, CG162, CG27, CG153, and CG168 play in biological processes, and preferably in disease states. Transgenic animals are useful as model systems to identify compounds that modulate lipid metabolism. Transgenic animals, preferably non-human mammals, are produced using methods as described in U.S. Pat. No 5,489,743 and PCT Publication No. WO94/28122, incorporated herein by reference.

[0123] Transgenic animals can be prepared wherein all or part of an CG122, CG179, CG95, CG121, CG162, CG27, CG153 or CG168 promoter is either activated or in activated to alter the level of expression of the CG122, CG179, CG95, CG121, CG162, CG27, CG153 or CG168 protein. Inactivation can be carried out using homologous recombination methods described above. Activation can be achieved by supplementing or even replacing the homologous promoter to provide for increased protein expression. The homologous promoter can be supplemented by insertion of one or more heterologous enhancer elements known to confer promoter activity in a particular tissue. The promoter may also be introduced into functional proximity to the recited genes by homologous recombination.

6. USES AND BIOLOGICAL ACTIVITY

[0124] The biological activity of a polypeptide of the invention may manifest as, e.g., apolipoprotein, lipase, or lipoprotein receptor signaling activity. The polynucleotides and proteins of the present invention are expected to exhibit one or more of the uses or biological activities (including those associated with assays cited herein) identified below. Uses or activities described for proteins of the present invention may be provided by administration or use of such proteins or by administration or use of polynucleotides encoding such proteins (such as, for example, in gene therapies or vectors suitable for introduction of DNA). The mechanism underlying the particular condition or pathology will dictate whether CG122, CG179, CG95, CG121, CG162, CG27, CG153 or CG168 polypeptides; polynucleotides; or modulators (activators and inhibitors) would be beneficial to the subject in need of treatment. Thus, “therapeutic compositions of the invention” include compositions comprising of polynucleotides or polypeptides of the invention or compounds and other substances that modulate the overall activity of the target CG122, CG179, CG95, CG121, CG162, CG27, CG153 or CG168 gene products, either at the level of target gene/protein expression or target protein activity. Such modulators include polypeptides, analogs, (variants), including fragments and fusion proteins, antibodies and other binding proteins; compounds that directly or indirectly activate or inhibit the apolipoprotein-like, lipase-like, or lipoprotein receptor-like polypeptides of the invention; and antisense polynucleotides and polynucleotides suitable for triple helix formation.

[0125] CG122 and CG179 are related to members of the apolipoprotein family which include apo AI, A-II, A-IV, B, CI, CII, CIII, D, E, H, J, L, and apo(a), among others. CG122 most closely resembles apo IV while CG179 is most similar to apo C. CG95, CG121, and CG162 are all putative lipases. CG95 shown greatest similarity to PLA₂, CG121 to PLC, and CG162 to LAL. CG27, CG153, and CG168 are related to the lipoprotein receptors LDL receptor, VLDL receptor, scavenger receptor, and LRP respectively.

[0126] Changes in lipoprotein metabolism that lead to atherosclerosis or coronary heart disease can be due to diet or to mutations in genes encoding proteins involved in lipid transport [Breslow (1993) Circ 87 suppl III: III-16-III-21]. A number of such mutations are found in genes encoding the apolipoprotein component of lipoproteins. For example, abnormalities in apo E lead to type III hyperlipidemias also known as dysbetalipoproteinemia. Mutations in apo B can cause heterozygous hypobetalipoproteinemia or familial defective apo B-100. Defects in apo A-I can lead to very low HDL cholesterol levels and premature coronary heart disease, or to the apo A-I_(Milano) disorder [Breslow (1993) Circ 87 suppl III: III-16-III-21; Beiseigel (1998) Eur Heart J Suppl A: A20-A23┘. Defects in other proteins that regulate lipid metabolisn such as LPL can lead to massive hyperglyceridaemias such as chylomicronaemias, mixed hyperlipidaemia, postprandial hyperlipidaemias, and to low HDL. Mutations in the LDL receptor can lead to severe hypercholesterolaemia. Tangier disease, caused by mutations in ABC1 (also known as CERP) causes abnormalities in cholesterol metabolism and can lead to premature coronary artery disease [Rust et al. (1999) Nat Genet 22:352-355; Brooks-Wilson et al. (1999) Nat Genet 22:336-345]]. Defects in LAL activity, important for the regulation of cellular lipid uptake, is the underlying cause of two heritable diseases: Wolman disease and cholesteryl ester storage disease (CESD). Some pateints with CESD are able to survive past middle age but show signs of premature atherosclerosis [Du et al. (1998) Mol Gen Meta 64:126-134]. Other disorders, such as hypertriglyceridemia, may also result from defects in proteins involved in lipid metabolism [Breslow (1993) Circ 87 suppl III: III-16-III-21; Beiseigel (1998) Eur Heart J Suppl A: A20-A23].

[0127] Increased levels of extracellular snpPLA₂ activity has been associated with numerous inflammatory conditions including atherosclerosis and other cardiovascular diseases. snpPLA₂ is found associated with SMCs in normal arteries as well as the intima of atherosclerotic arteries, macrophages, and the lipid core of atherosclerotic plaques. snpPLA₂ is anchored to the extracellular matrix of arterial walls by binding to sulfated glycosaminoglycans (GAG) on proteoglycans. Chondroitin-sulfate proteoglycans (CSPG), such as versican, is expressed in the tunica of normal arteries and in the intima of atherosclerotic arteries. LDL and snpPLA₂ are both bound to CSPGs bringing these molecules close together thus facilitating the rapid hydrolysis of LDL phospholipids into the pro-inflammatory lipid factors, FFA and lysophospholipids. This process decreases the number of phospholipids on the surface of LDL. Smaller LDL particles show greater affinity for GAG which prolongs the retention time of these lipoproteins in the arterial wall, thereby promoting and sustaining inflammatory responses in atherosclerotic lesions [Hurt-Camejo et al. (1997) Atherosclerosis 132:1-8].

[0128] The cytosolic phospholipase C family of enzymes include ten different mammalian isozymes that comprise three major subfamilies, PLC-β, PLC-γ, and PLC-δ. PLC-γ differs from the other members by inclusion of SH domains that mediate protein-protein interactions. PLC-γ is an intracellular signaling molecule which is stimulated by a variety of agonists including e.g. hormones, growth factors, etc., that mediates the hydrolysis of phophatidylinositol 4,5-bisphosphate (PIP₂) into the second messengers, inositol 1,4,5-trisphosphate (IP₃) and 1,2-diacylglycerol (DAG). IP₃ induces the release of intracellular Ca2+ ions and DAG activates protein kinase C (PKC) leading to number of different downstream cellular responses [Sekiya et a. (1999) Chem Phy Lip 98:3-11]. PIP₂ is also one of the activators of cytosolic phopholipase A₂ (cPLA₂). cPLA₂ is a member of a group of PLA₂ enzymes which also include calcium-independent PLA₂ (iPLA₂), and several secreted PLA₂s (sPLA₂). cPLA₂ releases arachidonic acid from membrane phospholipids such as 1-alkyl-2-archidonoyl-sn-glycero-3-phosphocholine, into the cytoplasm, in response to various stimuli that increase intracellular Ca²⁺ ion concentration and lead to the phosphorylation of cPLA₂ via the MAP kinase pathway. Arachidonic acid is the precursor of pro-inflammatory lipids which include the eicosanoids: leukotrienes, prostaglandins, and thromboxanes. Analysis of cPLA₂—deficient mice reveals that loss of this protein leads to a significant decrease in eicosanoid production revealing the important role of this protein in inflammatory responses. [Gijon et al. (1999) J Leuk Biol 65:330-336; Bayon et a. (1998) Cyto Cell Mol Therapy 4:275-286 ; Chaminade et al. (1999) Lipids 34 Suppl.:S49-S55].

[0129] Receptors that may be involved in the process of lipid accumulation include scavenger receptors expressed on macrophages and endothelial cells, and LRP and VLDL receptors expressed on SMCs [Greaves et al. (1998) Curr Opin Lipidol 9:425-432; Ylä-Herttuala (1996) Curr Opin Lipidol 7:292-297; Freeman (1997) Curr Opin Hematology 4:41-47]. Recent identification of scavenger receptors expressed by endothelial cells suggests that this cell type may also be involved in atherogenesis [Greaves et al. (1998) Curr Opin Lipidol 9:425-432; Hiltunen et al. (1998) Atherosclerosis 137 Suppl:S81-S88].

[0130] The LDL receptor gene family includes LDL receptor, VLDL receptor, LRP, LRP-2/Gp330/megalin, apoER2 or LR7/8B, and LR11/sorLA-1 receptor. Ligands for the LDL receptor include modified lipoproteins such as IDL and LDL. Although the LDL receptor is important in lipid metabolism in the liver and steroidogenic tissues, it is not expressed in atherosclerotic lesions. The VLDL receptor specifically bind apoE-containing VLDL and β-VLDL particles as well as Lp(a). The VLDL receptor is expressed in both endothelial and medial SMCs in nonnal arteries and is also expressed in macrophages in atherosclerotic arteries. LRP mediates uptake of LPL/apoE lipoprotein complex, apoE-enriched VLDL remnants, LPL, LPL-triglyceride-rich lipoprotein complexes, α2-macroglobulin-protease and other protease-antiprotease complexes. LRP is expressed in SMCs and macrophages found in both normal and atherosclerotic lesions. Neither LRP-2 nor apoER2 are expressed in arterial walls, thus these proteins are probably not directly involved in atherogenesis. However, these receptors may contribute to changes in the levels of various lipoproteins in the plasma, thus indirectly promoting artherogenesis. On the other hand, preliminary reports indicate that LR11 is expressed in SMCs of atherosclerotic arteries [Hiltunen et al. (1998) Atherosclerosis 137 Suppl: S81-S88]

[0131] Scavenger receptors are expressed on macrophages and specific endothelial cells and mediate the uptake and degradation of polyanionic ligands including modified LDL. Based on structural differences, these receptors are further divided into five classes. Class A scavenger receptors consist of SR-A which encodes three different isoforms (SR-AI, SR-AII, and SR-AIII) due to alternative splicing, and MARCO (macrophage receptor with collagenous structure), all of which bind acetylated LDL. SR-AI and SR-AII receptors are predominantly expressed in macrophages found in atherosclerotic lesions. The Class B scavenger receptors include CD36, SR-BI, an alternatively spliced form of SR-BI designated SR-BII, and the Drosophila croquemort. CD36 is expressed on platelets, macrophages, adipocytes, and specific endothelial cells. CD36 binds thrombospondin, collagen, anionic phospholipids, and oxidized LDL among others. SR-BI specifically binds HDL and is able to selectively uptake lipid from HDL thereby removing cholesterol from HDL. SR-BII also functions as an HDL receptor however, it is considerably less efficient in mediating cholesterol transport as compared to SR-BI. The Drosophila dSR-CI, which mediates acetylated LDL uptake by embryonic hemocytes/macrophages, is the only member of the class C scavenger receptors. Class D members include the murine macrosialin and its human homologue CD28. Both bind oxidized LDL and reside in the late endosomal compartment of monocytes and macrophages. Due to their intracellular location, it is speculated that these proteins function in the retention of modified LDL within the cell. The lectin-like oxidized LDL receptor (LOX-1) receptor expressed on endothelial cells defines the class E scavenger receptors and has been shown to preferentially bind oxidized LDL. Finally, class F consists of the scavenger receptor expressed by endothelial cells (SREC) which preferentially binds acetylated LDL. Experiments using knockout mice have verified a role for SR-A as well as other scavenger receptors in the development of atherosclerotic lesions [Greaves et al. (1998) Curr Opin Lipidol 9:425-432].

6.1. RESEARCH USES AND UTILITIES

[0132] The polynucleotides provided by the present invention can be used by the research community for various purposes. The polynucleotides can be used to express recombinant protein for analysis, characterization or therapeutic use; as markers for tissues in which the corresponding protein is preferentially expressed (either constitutively or at a particular stage of tissue differentiation or development or in disease states); as molecular weight markers on e.g. Southern gels; as chromosome markers or tags (when labeled) to identify chromosomes or to map related gene positions; to compare with endogenous DNA sequences in patients to identify potential genetic disorders; as probes to hybridize and thus discover novel, related DNA sequences; as a source of information to derive PCR primers for genetic fingerprinting; as a probe to “subtract-out” known sequences in the process of discovering other novel polynucleotides; for selecting and making oligomers for attachment to a “gene chip” or other support, including for examination of expression patterns; to raise anti-protein antibodies using DNA immunization techniques; and as an antigen to raise anti-DNA antibodies or elicit another immune response. Where the polynucleotide encodes a protein which binds or potentially binds to another protein (such as, for example, in a receptor-ligand interaction), the polynucleotide can also be used in interaction trap assays (such as, for example, that described in Gyuris et al., Cell 75:791-803 (1993)) to identify polynucleotides encoding the other protein with which binding occurs or to identify inhibitors of the binding interaction.

[0133] The proteins provided by the present invention can similarly be used in assays to determine biological activity, including in a panel of multiple proteins for high-throughput screening; to raise antibodies or to elicit another immune response; as a reagent (including the labeled reagent) in assays designed to quantitatively determine levels of the protein (or its receptor) in biological fluids; as markers for tissues in which the corresponding protein is preferentially expressed (either constitutively or at a particular stage of tissue differentiation or development or in a disease state); and, of course, to isolate correlative receptors or ligands. Where the protein binds or potentially binds to another protein (such as, for example, in a receptor-ligand interaction), the protein can be used to identify the other protein with which binding occurs or to identify inhibitors of the binding interaction. Proteins involved in these binding interactions can also be used to screen for peptide or small molecule inhibitors or agonists of the binding interaction.

[0134] Any or all of these research utilities are capable of being developed into reagent grade or kit format for commercialization as research products.

[0135] Methods for performing the uses listed above are well known to those skilled in the art. References disclosing such methods include without limitation “Molecular Cloning: A Laboratory Manual”, 2d ed., Cold Spring Harbor Laboratory Press, Sambrook, J., E. F. Fritsch and T. Maniatis eds., 1989, and “Methods in Enzymology: Guide to Molecular Cloning Techniques”, Academic Press, Berger, S. L. and A. R. Kimmel eds., 1987.

6.2. NUTRITIONAL USES

[0136] Polynucleotides and proteins of the present invention can also be used as nutritional sources or supplements. Such uses include without limitation use as a protein or amino acid supplement, use as a carbon source, use as a nitrogen source and use as a source of carbohydrate. In such cases the protein or polynucleotide of the invention can be added to the feed of a particular organism or can be administered as a separate solid or liquid preparation, such as in the form of powder, pills, solutions, suspensions or capsules. In the case of microorganisms, the protein or polynucleotide of the invention can be added to the medium in or on which the microorganism is cultured.

6.3. CYTOKINE AND CELL PROLIFERATION/DIFFERENTIATION ACTIVITY

[0137] A protein of the present invention may exhibit receptor signaling activity relating to cytokine, cell proliferation (either inducing or inhibiting) or cell differentiation (either inducing or inhibiting) activity or may induce production of other cytokines in certain cell populations. A polynucleotide of the invention can encode a polypeptide exhibiting such attributes. Many protein factors discovered to date, including all known cytokines, have exhibited activity in one or more factor-dependent cell proliferation assays, and hence the assays serve as a convenient confirmation of cytokine activity. The activity of therapeutic compositions of the present invention is evidenced by any one of a number of routine factor dependent cell proliferation assays for cell lines including, without limitation, 32D, DA2, DA1G, T10, B9, B9/11, BaF3, MC9/G, M+(preB M+), 2E8, RB5, DA1, 123, T1165, HT2, CTLL2, TF-1, Mo7e, CMK, HUVEC, and Caco. Therapeutic compositions of the invention can be used in the following:

[0138] Assays for T-cell or thymocyte proliferation include without limitation those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A. M. Kruisbeek, D. H. Margulies, E. M. Shevach, W. Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function 3.1-3.19; Chapter 7, Immunologic studies in Humans); Takai et al., J. Immunol. 137:3494-3500, 1986; Bertagnolli et al., J. Immunol. 145:1706-1712, 1990; Bertagnolli et al., Cellular Immunology 133:327-341, 1991; Bertagnolli, et al., I. Immunol. 149:3778-3783, 1992; Bowman et al., I. Immunol. 152:1756-1761, 1994.

[0139] Assays for cytokine production and/or proliferation of spleen cells, lymph node cells or thymocytes include, without limitation, those described in: Polyclonal T cell stimulation, Kruisbeek, A. M. and Shevach, E. M. In Current Protocols in Immunology. J. E. e.a. Coligan eds. Vol 1 pp. 3.12.1-3.12.14, John Wiley and Sons, Toronto. 1994; and Measurement of mouse and human interleukin-γ, Schreiber, R. D. In Current Protocols in Immunology. J. E. e.a. Coligan eds. Vol 1pp. 6.8.1-6.8.8, John Wiley and Sons, Toronto. 1994.

[0140] Assays for proliferation and differentiation of hematopoietic and lymphopoietic cells include, without limitation, those described in: Measurement of Human and Murine Interleukin 2 and Interleukin 4, Bottomly, K., Davis, L. S. and Lipsky, P. E. In Current Protocols in Immunology. J. E. e.a. Coligan eds. Vol 1 pp. 6.3.1-6.3.12, John Wiley and Sons, Toronto. 1991; deVries et al., J. Exp. Med. 173:1205-1211, 1991; Moreau et al., Nature 336:690-692, 1988; Greenberger et al., Proc. Natl. Acad. Sci. U.S.A. 80:2931-2938, 1983; Measurement of mouse and human interleukin 6—Nordan, R. In Current Protocols in Immunology. J. E. e.a. Coligan eds. Vol 1 pp. 6.6.1-6.6.5, John Wiley and Sons, Toronto. 1991; Smith et al., Proc. Natl. Aced. Sci. U.S.A. 83:1857-1861, 1986; Measurement of human Interleukin I 1—Bennett, F., Giannotti, J., Clark, S. C. and Turner, K. J. In Current Protocols in Immunology. J. E. e.a. Coligan eds. Vol 1 pp. 6.15.1 John Wiley and Sons, Toronto. 1991; Measurement of mouse and human Interleukin 9—Ciarletta, A., Giannotti, J., Clark, S. C. and Turner, K. J. In Current Protocols in Immunology. J. E. e.a. Coligan eds. Vol 1 pp. 6.13.1, John Wiley and Sons, Toronto. 1991.

[0141] Assays for T-cell clone responses to antigens (which will identify, among others, proteins that affect APC-T cell interactions as well as direct T-cell effects by measuring proliferation and cytokine production) include, without limitation, those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A. M. Kruisbeek, D. H. Margulies, E. M. Shevach, W Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function; Chapter 6, Cytokines and their cellular receptors; Chapter 7, Immunologic studies in Humans); Weinberger et al., Proc. Natl. Acad. Sci. USA 77:6091-6095, 1980; Weinberger et al., Eur. J. Immun. 11:405-411, 1981; Takai et al., J. Immunol. 137:3494-3500, 1986; Takai et al., J. Immunol. 140:508-512, 1988.

6.4. IMMUNE STIMULATING OR SUPPRESSING ACTIVITY

[0142] A protein of the present invention may also exhibit immune stimulating or immune suppressing activity, including without limitation the activities for which assays are described herein. A polynucleotide of the invention can encode a polypeptide involved in such activities. A protein or antibody, other binding partner, or other modulator of the invention may be useful in the treatment of various immune deficiencies and disorders (including severe combined immunodeficiency (SCID)), e.g., in regulating (up or down) growth and proliferation of T and/or B lymphocytes, as well as effecting the cytolytic activity of NK cells and other cell populations. These immune deficiencies may be genetic or be caused by viral (e.g., HIV) as well as bacterial or fungal infections, or may result from autoimmune disorders. More specifically, infectious diseases caused by viral, bacterial, fungal or other infection may be treatable using a protein, antibody, binding partner, or other modulator of the invention, including infections by HIV, hepatitis viruses, herpesviruses, mycobacteria, Leishmania spp., malaria spp. and various fungal infections such as candidiasis, as well as other conditions where a boost to the immune system generally may be desirable, e.g., in the treatment of cancer.

[0143] Autoimmune disorders which may involve a receptor protein of the present invention include, for example, connective tissue disease, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, autoimmune pulmonary inflammation, Guillain-Barre syndrome, autoimmune thyroiditis, insulin dependent diabetes mellitis, myasthenia gravis, graft-versus-host disease and autoimmune inflammatory eye disease. Such a receptor protein of the present invention may also to be involved in allergic reactions and conditions, such as asthma (particularly allergic asthma) or other respiratory problems.

[0144] Using the proteins, antibody, binding partners, or other modulators of the invention it may also be possible to modulate immune responses, in a number of ways. The immune response may be enhanced or suppressed. Down regulation may be in the form of inhibiting or blocking an immune response already in progress or may involve preventing the induction of an immune response. The functions of activated T cells may be inhibited by suppressing T cell responses or by inducing specific tolerance in T cells, or both. Immunosuppression of T cell responses is generally an active, non-antigen-specific, process which requires continuous exposure of the T cells to the suppressive agent. Tolerance, which involves inducing non-responsiveness or anergy in T cells, is distinguishable from immunosuppression in that it is generally antigen-specific and persists after exposure to the tolerizing agent has ceased. Operationally, tolerance can be demonstrated by the lack of a T cell response upon reexposure to specific antigen in the absence of the tolerizing agent.

[0145] Down regulating or preventing the immune response, e.g., preventing high level lymphokine synthesis by activated T cells, will be useful in situations of tissue, skin and organ transplantation and in graft-versus-host disease (GVHD). For example, blockage of T cell function should result in reduced tissue destruction in tissue transplantation. Typically, in tissue transplants, rejection of the transplant is initiated through its recognition as foreign by T cells, followed by an immune reaction that destroys the transplant. The administration of a molecule which inhibits or blocks the immune response (e.g. a receptor fragment, binding partner, or other modulator such as antisense polynucleotides) may act as an immunosuppressant.

[0146] The efficacy of particular immune response modulators in preventing organ transplant rejection or GVHD can be assessed using animal models that are predictive of efficacy in humans. Examples of appropriate systems which can be used include allogeneic cardiac grafts in rats and xenogeneic pancreatic islet cell grafts in mice, both of which have been used to examine the immunosuppressive effects of CTLA4Ig fusion proteins in vivo as described in Lenschow et al., Science 257:789-792 (1992) and Turka et al., Proc. Natl. Acad. Sci USA, 89:11102-11105 (1992). In addition, murine models of GVHD (see Paul ed., Fundamental Immunology, Raven Press, N.Y., 1989, pp. 846-847) can be used to determine the effect of blocking B lymphocyte antigen function in vivo on the development of that disease.

[0147] Blocking the inflammatory response may also be therapeutically useful for treating autoimmune diseases. Many autoimmune disorders are the result of inappropriate activation of T cells that are reactive against self tissue and which promote the production of cytokines and autoantibodies involved in the pathology of the diseases. Preventing the activation of autoreactive T cells may reduce or eliminate disease symptoms. Administration of reagents which block costimulation of T cells can be used to inhibit T cell activation and prevent production of autoantibodies or T cell-derived cytokines which may be involved in the disease process. Additionally, blocking reagents may induce antigen-specific tolerance of autoreactive r cells which could lead to long-term relief from the disease. The efficacy of blocking reagents in preventing or alleviating autoimmune disorders can be determined using a number of well-characterized animal models of human autoimmune diseases. Examples include murine experimental autoimmune encephalitis, systemic lupus erythmatosis in MRL/1pr/1pr mice or NZB hybrid mice, murine autoimmune collagen arthritis, diabetes mellitus in NOD mice and BB rats, and murine experimental myasthenia gravis (see Paul ed., Fundamental Immunology, Raven Press, New York, 1989, pp. 840-856).

[0148] Upregulation of immune responses, may also be useful in therapy. Upregulation of immune responses may be in the form of enhancing an existing immune response or eliciting an initial immune response. For example, enhancing an immune response may be useful in cases of viral infection such as influenza, the common cold, and encephalitis.

[0149] Alternatively, anti-viral immune responses may be enhanced in an infected patient by removing T cells from the patient, costimulating the T cells in vitro and reintroducing the in vitro activated T cells into the patient.

[0150] The activity of therapeutic compositions of the invention may, among other means, be measured by the following methods:

[0151] Suitable assays for thymocyte or splenocyte cytotoxicity include, without limitation, those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A. M. Kruisbeek, D. H. Margulies, E. M. Shevach, W. Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function 3.1-3.19; Chapter 7, Immunologic studies in Humans); Herrmann et al., Proc. Natl. Acad. Sci. USA 78:2488-2492, 1981; Herrmann et al., J. Immunol. 128:1968-1974, 1982; Handa et al., J. Immunol. 135:1564-1572, 1985; Takai et al., I. Immunol. 137:3494-3500, 1986; Takai et al., J. Immunol. 140:508-512, 1988; Herrmann et al., Proc. Natl. Acad. Sci. USA 78:2488-2492, 1981; Herrmann et al., J. Immunol. 128:1968-1974, 1982; Handa et al., J. Immunol. 135:1564-1572, 1985; Takai et al., J. Immunol. 137:3494-3500, 1986; Bowmanet al., J. Virology 61:1992-1998; Takai et al., J. Immunol. 140:508-512, 1988; Bertagnolli et al., Cellular Immunology 133:327-341, 1991; Brown et al., J. Immunol. 153:3079-3092, 1994.

[0152] Assays for T-cell-dependent immunoglobulin responses and isotype switching (which will identify, among others, proteins that modulate T-cell dependent antibody responses and that affect Th1/Th2 profiles) include, without limitation, those described in: Maliszewski, J. Immunol. 144:3028-3033, 1990; and Assays for B cell function: In vitro antibody production, Mond, J. J. and Brunswick, M. In Current Protocols in Immunology. J. E. e.a. Coligan eds. Vol 1 pp. 3.8.1-3.8.16, John Wiley and Sons, Toronto. 1994.

[0153] Mixed lymphocyte reaction (MLR) assays (which will identify, among others, proteins that generate predominantly Th1 and CTL responses) include, without limitation, those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A. M. Kruisbeek, D. H. Margulies, E. M. Shevach, W. Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function 3.1-3.19; Chapter 7, Immunologic studies in Humans); Takai et al., J. Immunol. 137:3494-3500, 1986; Takai et al., J. Immunol. 140:508-512, 1988; Bertagnolli et al., J. Immunol. 149:3778-3783, 1992.

[0154] Dendritic cell-dependent assays (which will identify, among others, proteins expressed by dendritic cells that activate naive T-cells) include, without limitation, those described in: Guery et al., J. Immunol. 134:536-544, 1995; Inaba et al., Journal of Experimental Medicine 173:549-559, 1991; Macatonia et al., Journal of Immunology 154:5071-5079, 1995; Porgador et al., Journal of Experimental Medicine 182:255-260, 1995; Nair et al., Journal of Virology 67:4062-4069, 1993; Huang et al., Science 264:961-965, 1994; Macatonia et al., Journal of Experimental Medicine 169:1255-1264, 1989; Bhardwaj et al., Journal of Clinical Investigation 94:797-807, 1994; and Inaba et al., Journal of Experimental Medicine 172:631-640 1990.

[0155] Assays for lymphocyte survival/apoptosis (which will identify, among others, proteins that prevent apoptosis after superantigen induction and proteins that regulate lymphocyte homeostasis) include, without limitation, those described in: Darzynkiewicz et al., Cytometry 13:795-808, 1992; Gorczyca et al., Leukemia 7:659-670, 1993; Gorczyca et al., Cancer Research 53:1945-1951, 1993; Itoh et al., Cell 66:233-243, 1991; Zacharchuk, Journal of Immunology 145:4037-4045, 1990; Zamai et al., Cytometry 14:891-897, 1993; Gorczyca et al., International Journal of Oncology 1:639-648, 1992.

[0156] Assays for proteins that influence early steps of T-cell commitment and development include, without limitation, those described in: Antica et al., Blood 84:111-117, 1994; Fine et al., Cellular Immunology 155:111-122, 1994; Galyet al., Blood 85:2770-2778, 1995; Toki et al., Proc. Nat. Acad Sci. USA 88:7548-7551, 1991.

6.5. HEMATOPOIESIS REGULATING ACTIVITY

[0157] A protein of the present invention may be involved in regulation of hematopoiesis and, consequently, in the treatment of myeloid or lymphoid cell deficiencies. Even marginal biological activity in support of colony forming cells or of factor-dependent cell lines indicates involvement in regulating hematopoiesis, e.g. in supporting the growth and proliferation of erythroid progenitor cells alone or in combination with other cytokines, thereby indicating utility, for example, in treating various anemias or for use in conjunction with irradiation/chemotherapy to stimulate the production of erythroid precursors and/or erythroid cells; in supporting the growth and proliferation of myeloid cells such as granulocytes and monocytes/macrophages (i.e., traditional CSF activity) useful, for example, in conjunction with chemotherapy to prevent or treat consequent myelo-suppression; in supporting the growth and proliferation of megakaryocytes and consequently of platelets thereby allowing prevention or treatment of various platelet disorders such as thrombocytopenia, and generally for use in place of or complimentary to platelet transfusions; and/or in supporting the growth and proliferation of hematopoietic stem cells which are capable of maturing to any and all of the above-mentioned hematopoietic cells and therefore find therapeutic utility in various stem cell disorders (such as those usually treated with transplantation, including, without limitation, aplastic anemia and paroxysmal nocturnal hemoglobinuria), as well as in repopulating the stem cell compartment post irradiation/chemotherapy, either in-vivo or ex-vivo (i.e., in conjunction with bone marrow transplantation or with peripheral progenitor cell transplantation (homologous or heterologous)) as normal cells or genetically manipulated for gene therapy.

[0158] Therapeutic compositions of the invention can be used in the following:

[0159] Suitable assays for proliferation and differentiation of various hematopoietic lines are cited above.

[0160] Assays for embryonic stem cell differentiation (which will identify, among others, proteins that influence embryonic differentiation hematopoiesis) include, without limitation, those described in: Johansson et al. Cellular Biology 15:141-151, 1995; Keller et al., Molecular and Cellular Biology 13:473-486, 1993; McClanahan et al., Blood 81:2903-2915, 1993.

[0161] Assays for stem cell survival and differentiation (which will identify, among others, proteins that regulate lyinpho-hematopoiesis) include, without limitation, those described in: Methylcellulose colony forming assays, Freshney, M. G. In Culture of Hematopoietic Cells. R. I. Freshney, et al. eds. Vol pp. 265-268, Wiley-Liss, Inc., New York, N.Y. 1994; Hirayama et al., Proc. Natl. Acad. Sci. USA 89:5907-5911, 1992; Primitive hematopoietic colony forming cells with high proliferative potential, McNiece, I. K. and Briddell, R. A. In Culture of Hematopoietic Cells. R. I. Freshney, et al. eds. Vol pp. 23-39, Wiley-Liss, Inc., New York, N.Y. 1994; Neben et al., Experimental Hematology 22:353-359, 1994; Cobblestone area forming cell assay, Ploemacher, R. E. In Culture of Hematopoietic Cells. R. I. Freshney, et al. eds. Vol pp. 1-21, Wiley-Liss, Inc., New York, N.Y. 1994; Long term bone marrow cultures in the presence of stromal cells, Spooncer, E., Dexter, M. and Allen, T. In Culture of Hematopoietic Cells. R. I. Freshney, et al. eds. Vol pp. 163-179, Wiley-Liss, Inc., New York, N.Y. 1994; Long term culture initiating cell assay, Sutherland, H. J. In Culture of Hematopoietic Cells. R. I. Freshney, et al. eds. Vol pp. 139-162, Wiley-Liss, Inc., New York, N.Y. 1994.

6.6. TISSUE GROWTH ACTIVITY

[0162] A protein of the present invention also may be involved in bone, cartilage, tendon, ligament and/or nerve tissue growth or regeneration, as well as in wound healing and tissue repair and replacement, and in healing of burns, incisions and ulcers.

[0163] For example, induction of cartilage and/or bone growth in circumstances where bone is not normally formed, has application in the healing of bone fractures and cartilage damage or defects in humans and other animals. Compositions of a protein, antibody, binding partner, or other modulator of the invention may have prophylactic use in closed as well as open fracture reduction and also in the improved fixation of artificial joints. De novo bone formation induced by an osteogenic agent contributes to the repair of congenital, trauma induced, or oncologic resection induced craniofacial defects, and also is useful in cosmetic plastic surgery.

[0164] A protein of this invention may also be involved in attracting bone-forming cells, stimulating growth of bone-forming cells, or inducing differentiation of progenitors of bone-forming cells. Treatment of osteoporosis, osteoarthritis, bone degenerative disorders, or periodontal disease, such as through stimulation of bone and/or cartilage repair or by blocking inflammation or processes of tissue destruction (collagenase activity, osteoclast activity, etc.) mediated by inflammatory processes may also be possible using the composition of the invention.

[0165] Another category of tissue regeneration activity that may involve the protein of the present invention is tendon/ligament formation. Induction of tendon/ligament-like tissue or other tissue formation in circumstances where such tissue is not normally formed, has application in the healing of tendon or ligament tears, deformities and other tendon or ligament defects in humans and other animals. Such a preparation employing a tendon/ligament-like tissue inducing protein may have prophylactic use in preventing damage to tendon or ligament tissue, as well as use in the improved fixation of tendon or ligament to bone or other tissues, and in repairing defects to tendon or ligament tissue. De novo tendon/ligament-like tissue formation induced by a composition of the present invention contributes to the repair of congenital, trauma induced, or other tendon or ligament defects of other origin, and is also useful in cosmetic plastic surgery for attachment or repair of tendons or ligaments. The compositions of the present invention may provide environment to attract tendon- or ligament-forming cells, stimulate growth of tendon- or ligament-forming cells, induce differentiation of progenitors of tendon- or ligament-forming cells, or induce growth of tendon/ligament cells or progenitors ex vivo for return in vivo to effect tissue repair. The compositions of the invention may also be useful in the treatment of tendinitis, carpal tunnel syndrome and other tendon or ligament defects. The compositions may also include an appropriate matrix and/or sequestering agent as a carrier as is well known in the art.

[0166] The compositions of the present invention may also be useful for proliferation of neural cells and for regeneration of nerve and brain tissue, i.e. for the treatment of central and peripheral nervous system diseases and neuropathies, as well as mechanical and traumatic disorders, which involve degeneration, death or trauma to neural cells or nerve tissue. More specifically, a composition may be used in the treatment of diseases of the peripheral nervous system, such as peripheral nerve injuries, peripheral neuropathy and localized neuropathies, and central nervous system diseases, such as Alzheimer's, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Shy-Drager syndrome. Further conditions which may be treated in accordance with the present invention include mechanical and traumatic disorders, such as spinal cord disorders, head trauma and cerebrovascular diseases such as stroke. Peripheral neuropathies resulting from chemotherapy or other medical therapies may also be treatable using a composition of the invention.

[0167] Compositions of the invention may also be useful to promote better or faster closure of non-healing wounds, including without limitation pressure ulcers, ulcers associated with vascular insufficiency, surgical and traumatic wounds, and the like.

[0168] Compositions of the present invention may also be involved in the generation or regeneration of other tissues, such as organs (including, for example, pancreas, liver, intestine, kidney, skin, endothelium), muscle (smooth, skeletal or cardiac) and vascular (including vascular endothelium) tissue, or for promoting the growth of cells comprising such tissues. Inhibition or modulation of fibrotic scarring may allow normal tissue to regenerate.

[0169] A composition of the present invention may also be useful for gut protection or regeneration and treatment of lung or liver fibrosis, reperfusion injury in various tissues, and conditions resulting from systemic cytokine damage.

[0170] A composition of the present invention may also be useful for promoting or inhibiting differentiation of tissues described above from precursor tissues or cells; or for inhibiting the growth of tissues described above.

[0171] Therapeutic compositions of the invention can be used in the following:

[0172] Assays for tissue generation activity include, without limitation, those described in: International Patent Publication No. WO95/16035 (bone, cartilage, tendon); International Patent Publication No. WO95/05846 (nerve, neuronal); International Patent Publication No. WO91/07491 (skin, endothelium).

[0173] Assays for wound healing activity include, without limitation, those described in: Winter, Epidermal Wound Healing, pps. 71-112 (Maibach, H. I. and Rovee, D. T., eds.), Year Book Medical Publishers, Inc., Chicago, as modified by Eaglstein and Mertz, J. Invest. Dermatol 71:382-84 (1978).

6.7. CHEMOTACTIC/CHEMOKINETIC ACTIVITY

[0174] A protein of the present invention may be involved in chemotactic or chemokinetic activity (e.g., act as a chemokine receptor) for mammalian cells, including, for example, monocytes, fibroblasts, neutrophils, T-cells, mast cells, eosinophils, epithelial and/or endothelial cells. A polynucleotide of the invention can encode a polypeptide exhibiting such attributes. Chemotactic and chemokinetic receptor activation can be used to mobilize or attract a desired cell population to a desired site of action. Chemotactic or chemokinetic compositions (e.g. proteins, antibodies, binding partners, or modulators of the invention) provide particular advantages in treatment of wounds and other trauma to tissues, as well as in treatment of localized infections. For example, attraction of lymphocytes, monocytes or neutrophils to tumors or sites of infection may result in improved immune responses against the tumor or infecting agent.

[0175] A protein or peptide has chemotactic activity for a particular cell population if it can stimulate, directly or indirectly, the directed orientation or movement of such cell population. Preferably, the protein or peptide has the ability to directly stimulate directed movement of cells. Whether a particular protein has chemotactic activity for a population of cells can be readily determined by employing such protein or peptide in any known assay for cell chemotaxis.

[0176] Therapeutic compositions of the invention can be used in the following:

[0177] Assays for chemotactic activity (which will identify proteins that induce or prevent chemotaxis) consist of assays that measure the ability of a protein to induce the migration of cells across a membrane as well as the ability of a protein to induce the adhesion of one cell population to another cell population. Suitable assays for movement and adhesion include, without limitation, those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A. M. Kruisbeek, D. H. Marguiles, E. M. Shevach, W. Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 6.12, Measurement of alpha and beta Chemokines 6.12.1-6.12.28; Taub et al. J. Clin. Invest. 95:1370-1376, 1995; Lind et al. APMIS 103:140-146, 1995; Muller et al Eur. J. Immunol. 25:1744-1748; Gruber et al. J. of Immunol. 152:5860-5867, 1994; Johnston et al. J. of Immunol. 153:1762-1768, 1994.

6.8. HEMOSTATIC AND THROMBOLYTIC ACTIVITY

[0178] A protein of the invention may also be involved in hemostatis or thrombolysis or thrombosis. A polynucleotide of the invention can encode a polypeptide exhibiting such attributes. Compositions may be useful in treatment of various coagulation disorders (including hereditary disorders, such as hemophilias) or to enhance coagulation and other hemostatic events in treating wounds resulting from trauma, surgery or other causes. A composition of the invention may also be useful for dissolving or inhibiting formation of thromboses and for treatment and prevention of conditions resulting therefrom (such as, for example, infarction of cardiac and central nervous system vessels (e.g., stroke).

[0179] Therapeutic compositions of the invention can be used in the following:

[0180] Assay for hemostatic and thrombolytic activity include, without limitation, those described in: Linet et al., J. Clin. Pharmacol. 26:131-140, 1986; Burdick et al., Thrombosis Res. 45:413-419, 1987; Humphrey et al., Fibrinolysis 5:71-79 (1991); Schaub, Prostaglandins 35:467-474, 1988.

6.10. RECEPTOR/LIGAND ACTIVITY

[0181] A protein of the present invention may also demonstrate activity as receptors, receptor ligands or inhibitors or agonists of receptor/ligand interactions. A polynucleotide of the invention can encode a polypeptide exhibiting such characteristics. Examples of such receptors and ligands include, without limitation, cytokine receptors and their ligands, receptor kinases and their ligands, receptor phosphatases and their ligands, receptors involved in cell-cell interactions and their ligands (including without limitation, cellular adhesion molecules (such as selecting, integrins and their ligands) and receptor/ligand pairs involved in antigen presentation, antigen recognition and development of cellular and humoral immune responses). Receptors and ligands are also useful for screening of potential peptide or small molecule inhibitors of the relevant receptor/ligand interaction. A protein of the present invention (including, without limitation, fragments of receptors and ligands) may themselves be useful as inhibitors of receptor/ligand interactions.

[0182] The activity of a protein of the invention may, among other means, be measured by the following methods:

[0183] Suitable assays for receptor-ligand activity include without limitation those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A. M. Kruisbeek, D. H. Margulies, E. M. Shevach, W. Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 7.28, Measurement of Cellular Adhesion under static conditions 7.28.1-7.28.22), Takai et al., Proc. Natl. Acad. Sci. U.S.A. 84:6864-6868, 1987; Bierer et al., J. Exp. Med. 168:1145-1156, 1988; Rosenstein et al., J. Exp. Med. 169:149-160 1989; Stoltenborg et al., J. Immunol. Methods 175:59-68, 1994; Stitt et al., Cell 80:661-670, 1995.

[0184] By way of example, the CG27, CG153 or CG168 polypeptides of the invention may be used as a lipoprotein receptor for a ligand(s) thereby transmitting the biological activity of that ligand(s). Ligands may be identified through binding assays, affinity chromatography, dihybrid screening assays, BIAcore assays, gel overlay assays, or other methods known in the art.

[0185] Studies characterizing drugs or proteins as agonist or antagonist or partial agonists or a partial antagonist require the use of other proteins as competing ligands. The polypeptides of the present invention or ligand(s) thereof may be labeled by being coupled to radioisotopes, colorimetric molecules or a toxin molecules by conventional methods. (“Guide to Protein Purification” Murray P. Deutscher (ed) Methods in Enzymology Vol. 182 (1990) Academic Press, Inc. San Diego). Examples of radioisotopes include, but are not limited to, tritium and carbon-14 . Examples of colorimetric molecules include, but are not limited to, fluorescent molecules such as fluorescamine, or rhodamine or other colorimetric molecules. Examples of toxins include, but are not limited, to ricin.

6.11 DRUG SCREENING

[0186] This invention is particularly useful for screening compounds by using the apolipoprotein, lipase or lipoprotein receptor polypeptides of the invention, particularly binding fragments, in any of a variety of drug screening techniques. The polypeptides employed in such a test may either be free in solution, affixed to a solid support, borne on a cell surface or located intracellularly. One method of drug screening utilizes eukaryotic or prokaryotic host cells which are stably transformed with recombinant nucleic acids expressing the desired polypeptide. Drugs are screened against such transformed cells in competitive binding assays. Such cells, either in viable or fixed form, can be used for standard binding assays. One may measure, for example, the formation of complexes between polypeptides of the invention and the agent being tested or examine the diminution in complex formation between the polypeptides and an appropriate cell line, which are well known in the art.

6.11.1 ASSAY FOR RECEPTOR ACTIVITY

[0187] The invention also provides methods to detect specific binding of a lipoprotein receptor of the invention to a binding partner polypeptide, or specific binding of an apolipoprotein of the invention to a binding partner polypeptide, in particular a receptor polypeptide. The art provides numerous assays particularly useful for identifying previously unknown binding partners for lipoprotein receptor polypeptides of the invention. For example, expression cloning using mammalian or bacterial cells, or dihybrid screening assays can be used to identify polynucleotides encoding binding partners. As another example, affinity chromatography with the appropriate immobilized polypeptide of the invention can be used to isolate polypeptides that recognize and bind a polypeptide of the invention. Ligands for lipoprotein receptor polypeptides of the invention can also be identified by adding lipoproteins or other exogenous ligands, or cocktails of lipoproteins to two cells populations that are genetically identical except for the expression of the lipoprotein receptor of the invention: one cell population expresses the lipoprotein receptor of the invention whereas the other does not. The response of the two cell populations to the addition of lipoprotein(s) are then compared. Alternatively, an expression library can be co-expressed with the lipoprotein receptor of the invention in cells and assayed for an autocrine response to identify potential ligand(s). As still another example, BlAcore assays, gel overlay assays, or other methods known in the art can be used to identify binding partner polypeptides.

[0188] The role of downstream intracellular signaling molecules in the signaling cascade of the lipoprotein receptor-like CG27, CG153 or CG168 can be determined. For example, a chimeric protein in which the cytoplasmic domain of CG27, CG153 or CG168 is fused to the extracellular portion of a protein, whose ligand has been identified, is produced in a host cell. The cell is then incubated with the ligand specific for the extracellular portion of the chimeric protein, thereby activating the chimeric receptor. Known downstream proteins involved in intracellular signaling can then be assayed for expected modifications i.e. phosphorylation. Other methods known to those in the art can also be used to identify signaling molecules involved in CG27, CG153 or CG168 receptor activity.

6.12. ANTI-INFLAMMATORY ACTIVITY

[0189] Compositions of the present invention may also exhibit anti-inflammatory activity. The anti-inflammatory activity may be achieved by providing a stimulus to cells involved in the inflammatory response, by inhibiting or promoting cell-cell interactions (such as, for example, cell adhesion), by inhibiting or promoting chemotaxis of cells involved in the inflammatory process, inhibiting or promoting cell extravasation, or by stimulating or suppressing production of other factors which more directly inhibit or promote an inflammatory response. Compositions with such activities can be used to treat inflammatory conditions including chronic or acute conditions), including without limitation intimation associated with infection (such as septic shock, sepsis or systemic inflammatory response syndrome (SIRS)), ischemia-reperfusion injury, endotoxin lethality, arthritis, complement-mediated hyperacute rejection, nephritis, cytokine or chemokine-induced lung injury, inflammatory bowel disease, Crohn's disease or resulting from over production of cytokines such as TNF or IL-1. Compositions of the invention may also be useful to treat anaphylaxis and hypersensitivity to an antigenic substance or material. Compositions of this invention may be utilized to prevent or treat condition such as, but not limited to, utilized, for example, as part of methods for the prevention and/or treatment of disorders involving sepsis, acute pancreatitis, endotoxin shock, cytokine induced shock, rheumatoid arthritis, chronic inflammatory arthritis, pancreatic cell damage from diabetes mellitus type 1, graft versus host disease, inflammatory bowel disease, inflamation associated with pulmonary disease, other autoimmune disease or inflammatory disease, an antiproliferative agent such as for acute or chronic mylegenous leukemia or in the prevention of premature labor secondary to intrauterine infections.

6.13. LEUKEMIAS

[0190] Leukemias and related disorders may be treated or prevented by administration of a therapeutic that promotes or inhibits function of the polynucleotides and/or polypeptides of the invention. Such leukemias and related disorders include but are not limited to acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, myeloblastic, promyelocytic, myelomonocytic, monotypic, erythroleukemia, chronic leukemia, chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia (for a review of such disorders, see Fishman et al., 1985, Medicine, 2d Ed., J. B. Lippincott Co., Philadelphia).

6.14. NERVOUS SYSTEM DISORDERS

[0191] Nervous system disorders, involving cell types which can be tested for efficacy of intervention with compounds that modulate the activity of the polynucleotides and/or polypeptides of the invention, and which can be treated upon thus observing an indication of therapeutic utility, include but are not limited to nervous system injuries, and diseases or disorders which result in either a disconnection of axons, a diminution or degeneration of neurons, or demyelination. Nervous system lesions which may be treated in a patient (including human and non-human mammalian patients) according to the invention include but are not limited to the following lesions of either the central (including spinal cord, brain) or peripheral nervous systems:

[0192] (i) traumatic lesions, including lesions caused by physical injury or associated with surgery, for example, lesions which sever a portion of the nervous system, or compression injuries;

[0193] (ii) ischemic lesions, in which a lack of oxygen in a portion of the nervous system results in neuronal injury or death, including cerebral infarction or ischemia, or spinal cord infarction or ischemia;

[0194] (iii) infectious lesions, in which a portion of the nervous system is destroyed or injured as a result of infection, for example, by an abscess or associated with infection by human immunodeficiency virus, herpes zoster, or herpes simplex virus or with Lyme disease, tuberculosis, syphilis;

[0195] (iv) degenerative lesions, in which a portion of the nervous system is destroyed or injured as a result of a degenerative process including but not limited to degeneration associated with Parkinson's disease, Alzheimer's disease, Huntington's chorea, or amyotrophic lateral sclerosis;

[0196] (v) lesions associated with nutritional diseases or disorders, in which a portion of the nervous system is destroyed or injured by a nutritional disorder or disorder of metabolism including but not limited to, vitamin B12 deficiency, folic acid deficiency, Wernicke disease, tobacco-alcohol amblyopia, Marchiafava-Bignami disease (primary degeneration of the corpus callosum), and alcoholic cerebellar degeneration;

[0197] (vi) neurological lesions associated with systemic diseases including but not limited to diabetes (diabetic neuropathy, Bell's palsy), systemic lupus erythematosus, carcinoma, or sarcoidosis;

[0198] (vii) lesions caused by toxic substances including alcohol, lead, or particular neurotoxins; and

[0199] (viii) demyelinated lesions in which a portion of the nervous system is destroyed or injured by a demyelinating disease including but not limited to multiple sclerosis, human immunodeficiency virus-associated myelopathy, transverse myelopathy or various etiologies, progressive multifocal leukoencephalopathy, and central pontine myelinolysis.

[0200] Therapeutics which are useful according to the invention for treatment of a nervous system disorder may be selected by testing for biological activity in promoting the survival or differentiation of neurons. For example, and not by way of limitation, therapeutics which elicit any of the following effects may be useful according to the invention:

[0201] (i) increased survival time of neurons in culture;

[0202] (ii) increased sprouting of neurons in culture or in vivo;

[0203] (iii) increased production of a neuron-associated molecule in culture or in vivo, e.g., choline acetyltransferase or acetylcholinesterase with respect to motor neurons; or

[0204] (iv) decreased symptoms of neuron dysfunction in vivo.

[0205] Such effects may be measured by any method known in the art. In preferred, non-limiting embodiments, increased survival of neurons may be measured by the method set forth in Arakawa et al. (1990, J. Neurosci. 10:3507-3515); increased sprouting of neurons maybe detected by methods set forth in Pestronk et al. (1980, Exp. Neurol. 70:65-82) or Brown et al. (1981, Ann. Rev. Neurosci. 4:17-42); increased production of neuron-associated molecules may be measured by bioassay, enzymatic assay, antibody binding, Northern blot assay, etc., depending on the molecule to be measured; and motor neuron dysfunction may be measured by assessing the physical manifestation of motor neuron disorder, e.g., weakness, motor neuron conduction velocity, or functional disability.

[0206] In a specific embodiment, motor neuron disorders that may be treated according to the invention include but are not limited to disorders such as infarction, infection, exposure to toxin, trauma, surgical damage, degenerative disease or malignancy that may affect motor neurons as well as other components of the nervous system, as well as disorders that selectively affect neurons such as amyotrophic lateral sclerosis, and including but not limited to progressive spinal muscular atrophy, progressive bulbar palsy, primary lateral sclerosis, infantile and juvenile muscular atrophy, progressive bulbar paralysis of childhood (Fazio-Londe syndrome), poliomyelitis and the post polio syndrome, and Hereditary Motorsensory Neuropathy (Charcot-Marie-Tooth Disease).

6.15. OTHER ACTIVITIES

[0207] A protein of the invention may also exhibit or be involved in one or more of the following additional activities or effects: inhibiting the growth, infection or function of, or killing, infectious agents, including, without limitation, bacteria, viruses, fungi and other parasites; effecting (suppressing or enhancing) bodily characteristics, including, without limitation, height, weight, hair color, eye color, skin, fat to lean ratio or other tissue pigmentation, or organ or body part size or shape (such as, for example, breast augmentation or diminution, change in bone form or shape); effecting biorhythms or caricadic cycles or rhythms; effecting the fertility of male or female subjects; effecting the metabolism, catabolism, anabolism, processing, utilization, storage or elimination of dietary fat, lipid, protein, carbohydrate, vitamins, minerals, co-factors or other nutritional factors or component(s); effecting behavioral characteristics, including, without limitation, appetite, libido, stress, cognition (including cognitive disorders), depression (including depressive disorders) and violent behaviors; providing analgesic effects or other pain reducing effects; promoting differentiation and growth of embryonic stem cells in lineages other than hematopoietic lineages; hormonal or endocrine activity; in the case of enzymes, correcting deficiencies of the enzyme and treating deficiency-related diseases; treatment of hyperproliferative disorders (such as, for example, psoriasis); immunoglobulin-like activity (such as, for example, the ability to bind antigens or complement); and the ability to act as an antigen in a vaccine composition to raise an immune response against such protein or another material or entity which is cross-reactive with such protein.

6.16 IDENTIFICATION OF POLYMORPHISMS

[0208] The demonstration of polymorphisms makes possible the identification of such polymorphisms in human subjects and the pharmacogenetic use of this information for diagnosis and treatment. Such polymorphisms may be associated with, e.g., differential predisposition or susceptibility to various disease states (such as disorders involving inflammation or immune response) or a differential response to drug administration, and this genetic information can be used to tailor preventive or therapeutic treatment appropriately. For example, the existence of a polymorphism associated with a predisposition to inflammation or autoimmune disease makes possible the diagnosis of this condition in humans by identifying the presence of the polymorphism.

[0209] Polymorphisms can be identified in a variety of ways known in the art which all generally involve obtaining a sample from a patient, analyzing DNA from the sample, optionally involving isolation or amplification of the DNA, and identifying the presence of the polymorphism in the DNA. For example, PCR may be used to amplify an appropriate fragment of genomic DNA which may then be sequenced. Alternatively, the DNA may be subjected to allele-specific oligonucleotide hybridization (in which appropriate oligonucleotides are hybridized to the DNA under conditions permitting detection of a single base mismatch) or to a single nucleotide extension assay (in which an oligonucleotide that hybridizes immediately adjacent to the position of the polymorphism is extended with one or more labeled nucleotides). In addition, traditional restriction fragment length polymorphism analysis (using restriction enzymes that provide differential digestion of the genomic DNA depending on the presence or absence of the polymorphism) may be performed.

[0210] Alternatively a polymorphism resulting in a change in the amino acid sequence could also be detected by detecting a corresponding change in amino acid sequence of the protein, e.g., by an antibody specific to the variant sequence.

6.17 CANCER DIAGNOSIS AND THERAPY

[0211] Polypeptides of the invention may be involved in cancer cell generation, proliferation or metastasis. Detection of the presence or amount of polynucleotides or polypeptides of the invention may be useful for the diagnosis and/or prognosis of one or more types of cancer. For example, the presence or increased expression of a polynucleotide/polypeptide of the invention may indicate a hereditary risk of cancer, a precancerous condition, or an ongoing malignancy. Conversely, a defect in the gene or absence of the polypeptide may be associated with a cancer condition. Identification of single nucleotide polymorphisms associated with cancer or a predisposition to cancer may also be useful for diagnosis or prognosis.

[0212] Cancer treatments promote tumor regression by inhibiting tumor cell proliferation, inhibiting angiogenesis (growth of new blood vessels that is necessary to support tumor growth) and/or prohibiting metastasis by reducing tumor cell motility or invasiveness. Therapeutic compositions of the invention may be effective in adult and pediatric oncology including in solid phase tumors/malignancies, locally advanced tumors, human soft tissue sarcomas, metastatic cancer, including lymphatic metastases, blood cell malignancies including multiple myeloma, acute and chronic leukemias, and lymphomas, head and neck cancers including mouth cancer, larynx cancer and thyroid cancer, lung cancers including small cell carcinoma and non-small cell cancers, breast cancers including small cell carcinoma and ductal carcinoma, gastrointestinal cancers including esophageal cancer, stomach cancer, colon cancer, colorectal cancer and polyps associated with colorectal neoplasia, pancreatic cancers, liver cancer, urologic cancers including bladder cancer and prostate cancer, malignancies of the female genital tract including ovarian carcinoma, uterine (including endometrial) cancers, and solid tumor in the ovarian follicle, kidney cancers including renal cell carcinoma, brain cancers including intrinsic brain tumors, neuroblastoma, astrocytic brain tumors, gliomas, metastatic tumor cell invasion in the central nervous system, bone cancers including osteomas, skin cancers including malignant melanoma, tumor progression of human skin keratinocytes, squamous cell carcinoma, basal cell carcinoma, hemangiopericytoma and Karposi's sarcoma.

[0213] Polypeptides, polynucleotides, or modulators of polypeptides of the invention (including inhibitors and stimulators of the biological activity of the polypeptide of the invention) may be administered to treat cancer. Therapeutic compositions can be administered in therapeutically effective dosages alone or in combination with adjuvant cancer therapy such as surgery, chemotherapy, radiotherapy, thermotherapy, and laser therapy, and may provide a beneficial effect, e.g. reducing tumor size, slowing rate of tumor growth, inhibiting metastasis, or otherwise improving overall clinical condition, without necessarily eradicating the cancer.

[0214] The composition can also be administered in therapeutically effective amounts as a portion of an anti-cancer cocktail. An anti-cancer cocktail is a mixture of the polypeptide or modulator of the invention with one or more anti-cancer drugs in addition to a pharmaceutically acceptable carrier for delivery. The use of anti-cancer cocktails as a cancer treatment is routine. Anti-cancer drugs that are well known in the art and can be used as a treatment in combination with the polypeptide or modulator of the invention include: Actinomycin D, Aminoglutethimide, Asparaginase, Bleomycin, Busulfan, Carboplatin, Carmustine, Chlorambucil, Cisplatin (cis-DDP), Cyclophosphamide, Cytarabine HCl (Cytosine arabinoside), Dacarbazine, Dactinomycin, Daunorubicin HCl, Doxorubicin HCl, Estramustine phosphate sodium, Etoposide (V16-213), Floxuridine, 5-Fluorouracil (5-Fu), Flutamide, Hydroxyurea (hydroxycarbamide), Ifosfamide, Interferon Alpha-2a, Interferon Alpha-2b, Leuprolide acetate (LHRH-releasing factor analog), Lomustine, Mechlorethamine HCl (nitrogen mustard), Melphalan, Mercaptopurine, Mesna, Methotrexate (MTX), Mitomycin, Mitoxantrone HCl, Octreotide, Plicamycin, Procarbazine HCl, Streptozocin, Tamoxifen citrate, Thioguanine, Thiotepa, Vinblastine sulfate, Vincristine sulfate, Amsacrine, Azacitidine, Hexamethylmelamine, Interleukin-2, Mitoguazone, Pentostatin, Semustine, Teniposide, and Vindesine sulfate.

[0215] In addition, therapeutic compositions of the invention may be used for prophylactic treatment of cancer. There are hereditary conditions and/or environmental situations (e.g. exposure to carcinogens) known in the art that predispose an individual to developing cancers. Under these circumstances, it may be beneficial to treat these individuals with therapeutically effective doses of the polypeptide of the invention to reduce the risk of developing cancers.

[0216] In vitro models can be used to determine the effective doses of the polypeptide of the invention as a potential cancer treatment. These in vitro models include proliferation assays of cultured tumor cells, growth of cultured tumor cells in soft agar (see Freshney, (1987) Culture of Animal Cells: A Manual of Basic Technique, Wily-Liss, New York, N.Y. Ch 18 and Ch 21), tumor systems in nude mice as described in Giovanella et al., J. Natl. Can. Inst., 52: 921-30 (1974), mobility and invasive potential of tumor cells in Boyden Chamber assays as described in Pilkington et al., Anticancer Res., 17: 4107-9 (1997), and angiogenesis assays such as induction of vascularization of the chick chorioallantoic membrane or induction of vascular endothelial cell migration as described in Ribatta et al., Intl. J. Dev. Biol., 40: 1189-97 (1999) and Li et al., Clin. Exp. Metastasis, 17:423-9 (1999) respectively. Suitable tumor cells lines are available, e.g. from American Type Tissue Culture Collection catalogs.

7. THERAPEUTIC METHODS

[0217] The compositions (including polypeptide fragments, analogs, variants and antibodies or other binding partners or modulators including antisense polynucleotides) of the invention have numerous applications in a variety of therapeutic methods. Examples of therapeutic applications include, but are not limited to, those exemplified below.

7.1 SEPSIS

[0218] One embodiment of the invention is the administration of an effective amount of compositions of the invention to individuals that are at a high risk of developing sepsis, or that have developed sepsis. An example of the former category are patients about to undergo surgery. While the mode of administration is not particularly important, parenteral administration is preferred because of the rapid progression of sepsis, and thus, the need to have the inhibitor disseminate quickly throughout the body. Thus, the preferred mode of administration is to deliver an I.V. bolus slightly before, during, or after surgery. The dosage of the compositions of the invention will normally be determined by the prescribing physician. It is to be expected that the dosage will vary according to the age, weight and response of the individual patient. Typically, where a protein is being administered, the amount of inhibitor administered per dose will be in the range of about 0.1 to 25 mg/kg of body weight, with the preferred dose being about 0.1 to 10 mg/kg of patient body weight. For parenteral administration, the compositions of the invention may be formulated in an injectable form that includes a pharmaceutically acceptable parenteral vehicle. Such vehicles are well known in the art and examples include water, saline, Ringer's solution, dextrose solution, and solutions consisting of small amounts of the human serum albumin. The vehicle may contain minor amounts of additives that maintain the isotonicity and stability of the inhibitor. The preparation of such solutions is within the skill of the art. Typically, the cytokine inhibitor will be formulated in such vehicles at a concentration of about 1-8 mg/ml to about 10 mg/ml.

7.2 ARTHRITIS AND INFLAMMATION

[0219] The immunosuppressive effects of the compositions of the invention against rheumatoid arthritis is determined in an experimental animal model system. The experimental model system is adjuvant induced arthritis in rats, and the protocol is described by J. Holoshitz, et at., 1983, Science, 219:56, or by B. Waksman et al., 1963, Int. Arch. Allergy Appl. Immunol., 23:129. Induction of the disease can be caused by a single injection, generally intradermally, of a suspension of killed Mycobacterium tuberculosis in complete Freund's adjuvant (CFA). The route of injection can vary, but rats may be injected at the base of the tail with an adjuvant mixture. The inhibitor is administered in phosphate buffered solution (PBS) at a dose of about 1-5 mg/kg. The control consists of administering PBS only.

[0220] The procedure for testing the effects of the test compound would consist of intradermally injecting killed Mycobacterium tuberculosis in CFA followed by immediately administering the inhibitor and subsequent treatment every other day until day 24. At 14, 15, 18, 20, 22, and 24 days after injection of Mycobacterium CFA, an overall arthritis score may be obtained as described by J. Holoskitz above. An analysis of the data would reveal that the test compound would have a dramatic affect on the swelling of the joints as measured by a decrease of the arthritis score.

7.4 PHARMACEUTICAL FORMULATIONS AND ROUTES OF ADMINISTRATION

[0221] A protein of the present invention (from whatever source derived, including without limitation from recombinant and non-recombinant sources and including antibodies and other binding partners of the polypeptides of the invention) may be administered to a patient in need, by itself, or in pharmaceutical compositions where it is mixed with suitable carriers or excipient(s) at doses to treat or ameliorate a variety of disorders. Such a composition may also contain (in addition to protein and a carrier) diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The term “pharmaceutically acceptable” means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredient(s). The characteristics of the carrier will depend on the route of administration. The pharmaceutical composition of the invention may also contain cytokines, lymphokines, or other hemaiopoietic factors such as M-CSF, GM-CSF, TNF, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IFN, TNF0, TNF1, TNF2, G-CSF, Meg-CSF, GM-CSF, thrombopoietin, stem cell factor, and erythropoietin. In further compositions, proteins of the invention may be combined with other agents beneficial to the treatment of the bone and/or cartilage defect, wound, or tissue in questions. These agents include various growth factors such as epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transforming growth factors (TGF-αand TGF-β), insulin-like growth factor (IGF), as well as cytokines described herein.

[0222] The pharmaceutical composition may further contain other agents which either enhance the activity of the protein or compliment its activity or use in treatment. Such additional factors and/or agents may be included in the pharmaceutical composition to produce a synergistic effect with protein of the invention, or to minimize side effects. Conversely, protein of the present invention may be included in formulations of the particular cytokine, lymphokine, other hematopoietic factor, thrombolytic or anti-thrombotic factor, or anti-inflammatory agent to minimize side effects of the cytokine, lymphokine, other hematopoietic factor, thrombolytic or anti-thrombotic factor, or anti-inflammatory agent. A protein of the present invention may be active in multimers (e.g., heterodimers or homodimers) or complexes with itself or other proteins. As a result, pharmaceutical compositions of the invention may comprise a protein of the invention in such multimeric or complexed form.

[0223] As an alternative to being included in a pharmaceutical composition of the invention including a first protein, a second protein or a therapeutic agent may be concurrently administered with the first protein.

[0224] Techniques for formulation and administration of the compounds of the instant application may be found in “Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa., latest edition. A therapeutically effective dose further refers to that amount of the compound sufficient to result in amelioration of symptoms, e.g., treatment, healing, prevention or amelioration of the relevant medical condition, or an increase in rate of treatment, healing, prevention or amelioration of such conditions. When applied to an individual active ingredient, administered alone, a therapeutically effective dose refers to that ingredient alone. When applied to a combination, a therapeutically effective dose refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.

[0225] In practicing the method of treatment or use of the present invention, a therapeutically effective amount of protein of the present invention is administered to a mammal having a condition to be treated. Protein of the present invention may be administered in accordance with the method of the invention either alone or in combination with other therapies such as treatments employing cytokines, lymphokines or other hematopoietic factors. When co-administered with one or more cytokines, lymphokines or other hematopoietic factors, protein of the present invention may be administered either simultaneously with the cytokine(s), lymphokine(s), other hematopoietic factor(s), thrombolytic or anti-thrombotic factors, or sequentially. If administered sequentially, the attending physician will decide on the appropriate sequence of administering protein of the present invention in combination with cytokine(s), lymphokine(s), other hematopoietic factor(s), thrombolytic or anti-thrombotic factors.

7.5. ROUTES OF ADMINISTRATION

[0226] Suitable routes of administration may, for example, include oral, rectal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections. Administration of protein of the present invention used in the pharmaceutical composition or to practice the method of the present invention can be carried out in a variety of conventional ways, such as oral ingestion, inhalation, topical application or cutaneous, subcutaneous, intraperitoneal, parenteral or intravenous injection. Intravenous administration to the patient is preferred.

[0227] Alternately, one may administer the compound in a local rather than systemic manner, for example, via injection of the compound directly into a arthritic joints or in fibrotic tissue, often in a depot or sustained release formulation. In order to prevent the scarring process frequently occurring as complication of glaucoma surgery, the compounds may be administered topically, for example, as eye drops. Furthermore, one may administer the drug in a targeted drug delivery system, for example, in a liposome coated with a specific antibody, targeting, for example, arthritic or fibrotic tissue. The liposomes will be targeted to and taken up selectively by the afflicted tissue.

7.6. COMPOSITIONS/FORMULATIONS

[0228] Pharmaceutical compositions for use in accordance with the present invention thus may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. These pharmaceutical compositions may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. Proper formulation is dependent upon the route of administration chosen. When a therapeutically effective amount of protein of the present invention is administered orally, protein of the present invention will be in the form of a tablet, capsule, powder, solution or elixir. When administered in tablet form, the pharmaceutical composition of the invention may additionally contain a solid carrier such as a gelatin or an adjuvant. The tablet, capsule, and powder contain from about 5 to 95% protein of the present invention, and preferably from about 25 to 90% protein of the present invention. When administered in liquid form, a liquid carrier such as water, petroleum, oils of animal or plant origin such as peanut oil, mineral oil, soybean oil, or sesame oil, or synthetic oils may be added. The liquid form of the pharmaceutical composition may further contain physiological saline solution, dextrose or other saccharide solution, or glycols such as ethylene glycol, propylene glycol or polyethylene glycol. When administered in liquid form, the pharmaceutical composition contains from about 0.5 to 90% by weight of protein of the present invention, and preferably from about 1 to 50% protein of the present invention.

[0229] When a therapeutically effective amount of protein of the present invention is administered by intravenous, cutaneous or subcutaneous injection, protein of the present invention will be in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable protein solutions, having due regard to pH, isotonicity, stability, and the like, is within the skill in the art. A preferred pharmaceutical composition for intravenous, cutaneous, or subcutaneous injection should contain, in addition to protein of the present invention, an isotonic vehicle such as Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, Lactated Ringer's Injection, or other vehicle as known in the art. The pharmaceutical composition of the present invention may also contain stabilizers, preservatives, buffers, antioxidants, or other additives known to those of skill in the art. For injection, the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[0230] For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0231] Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0232] For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.

[0233] Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0234] The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides. In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0235] A pharmaceutical carrier for the hydrophobic compounds of the invention is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. The cosolvent system may be the VPD co-solvent system. VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. The VPD co-solvent system (VPD:5W) consists of VPD diluted 1:1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration. Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose. Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various types of sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.

[0236] The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. Many of the compounds of the invention may be provided as salts with pharmaceutically compatible counterions. Such pharmaceutically acceptable base addition salts are those salts which retain the biological effectiveness and properties of the free acids and which are obtained by reaction with inorganic or organic bases such as sodium hydroxide, magnesium hydroxide, ammonia, trialkylamine, dialkylamine, monoalkylamine, dibasic amino acids, sodium acetate, potassium benzoate, triethanol amine and the like.

[0237] The pharmaceutical composition of the invention may be in the form of a complex of the protein(s) of present invention along with protein or peptide antigens. The protein and/or peptide antigen will deliver a stimulatory signal to both B and T lymphocytes. B lymphocytes will respond to antigen through their surface immunoglobulin receptor. T lymphocytes will respond to antigen through the T cell receptor (TCR) following presentation of the antigen by MHC proteins. MHC and structurally related proteins including those encoded by class I and class II MHC genes on host cells will serve to present the peptide antigen(s) to T lymphocytes. The antigen components could also be supplied as purified MHC-peptide complexes alone or with co-stimulatory molecules that can directly signal T cells. Alternatively antibodies able to bind surface immunoglobulin and other molecules on B cells as well as antibodies able to bind the TCR and other molecules on T cells can be combined with the pharmaceutical composition of the invention. The pharmaceutical composition of the invention may be in the form of a liposome in which protein of the present invention is combined, in addition to other pharmaceutically acceptable carriers, with amphipathic agents such as lipids which exist in aggregated form as micelles, insoluble monolayers, liquid crystals, or lamellar layers in aqueous solution. Suitable lipids for liposomal formulation include, without limitation, monoglycerides, diglycerides, sulfatides, lysolecithin, phospholipids, saponin, bile acids, and the like. Preparation of such liposomal formulations is within the level of skill in the art, as disclosed, for example, in U.S. Pat. Nos. 4,235,871; 4,501,728; 4,837,028; and 4,737,323, all of which are incorporated herein by reference.

[0238] The amount of protein of the present invention in the pharmaceutical composition of the present invention will depend upon the nature and severity of the condition being treated, and on the nature of prior treatments which the patient has undergone. Ultimately, the attending physician will decide the amount of protein of the present invention with which to treat each individual patient. Initially, the attending physician will administer low doses of protein of the present invention and observe the patient's response. Larger doses of protein of the present invention may be administered until the optimal therapeutic effect is obtained for the patient, and at that point the dosage is not increased further. It is contemplated that the various pharmaceutical compositions used to practice the method of the present invention should contain about 0.01 μg to about 100 mg (preferably about 0.1 μg to about 10 mg, more preferably about 0.1 μg to about 1 mg) of protein of the present invention per kg body weight. If desired, the therapeutic method includes administering the composition topically, systematically, or locally as an implant or device. When administered, the therapeutic composition for use in this invention is, of course, in a pyrogen-free, physiologically acceptable form. Further, the composition may desirably be encapsulated or injected in a viscous form for delivery to the site of bone, cartilage or tissue damage. Topical administration may be suitable for wound healing and tissue repair. Therapeutically useful agents other than a protein of the invention which may also optionally be included in the composition as described above, may alternatively or additionally, be administered simultaneously or sequentially with the composition in the methods of the invention. Preferably for bone and/or cartilage formation, the composition would include a matrix capable of delivering the protein-containing composition to the site of bone and/or cartilage damage, providing a structure for the developing bone and cartilage and optimally capable of being resorbed into the body. Such matrices may be formed of materials presently in use for other implanted medical applications.

[0239] The choice of matrix material is based on biocompatibility, biodegradability, mechanical properties, cosmetic appearance and interface properties. The particular application of the compositions will define the appropriate formulation. Potential matrices for the compositions may be biodegradable and chemically defined calcium sulfate, tricalcium phosphate, hydroxyapatite, polylactic acid, polyglycolic acid and polyanhydrides. Other potential materials are biodegradable and biologically well-defined, such as bone or dermal collagen. Further matrices are comprised of pure proteins or extracellular matrix components. Other potential matrices are nonbiodegradable and chemically defined, such as sintered hydroxyapatite, bioglass, aluminates, or other ceramics. Matrices may be comprised of combinations of any of the above mentioned types of material, such as polylactic acid and hydroxyapatite or collagen and tricalcium phosphate. The bioceramics may be altered in composition, such as in calcium-aluminate-phosphate and processing to alter pore size, particle size, particle shape, and biodegradability. Presently preferred is a 50:50 (mole weight) copolymer of lactic acid and glycolic acid in the form of porous particles having diameters ranging from 150 to 800 microns. In some applications, it will be useful to utilize a sequestering agent, such as carboxymethyl cellulose or autologous blood clot, to prevent the protein compositions from disassociating from the matrix.

[0240] A preferred family of sequestering agents is cellulosic materials such as alkylcelluloses (including hydroxyalkylcelluloses), including methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl-methylcellulose, and carboxymethylcellulose, the most preferred being cationic salts of carboxymethylcellulose (CMC). Other preferred sequestering agents include hyaluronic acid, sodium alginate, poly(ethylene glycol), polyoxyethylene oxide, carboxyvinyl polymer and poly(vinyl alcohol). The amount of sequestering agent useful herein is 0.5-20 wt %, preferably 1-10 wt % based on total formulation weight, which represents the amount necessary to prevent desorbtion of the protein from the polymer matrix and to provide appropriate handling of the composition, yet not so much that the progenitor cells are prevented from infiltrating the matrix, thereby providing the protein the opportunity to assist the fracture repair activity of the progenitor cells.

[0241] The therapeutic compositions are also presently valuable for veterinary applications. Particularly domestic animals and thoroughbred horses, in addition to humans, are desired patients for such treatment with proteins of the present invention. The dosage regimen of a protein-containing pharmaceutical composition to be used in tissue regeneration will be determined by the attending physician considering various factors which modify the action of the proteins, e.g., amount of tissue weight desired to be formed, the site of damage, the condition of the damaged tissue, the size of a wound, type of damaged tissue (e.g., bone), the patient's age, sex, and diet, the severity of any infection, time of administration and other clinical factors. The dosage may vary with the type of matrix used in the reconstitution and with inclusion of other proteins in the pharmaceutical composition. For example, the addition of other known growth factors, such as IGF I (insulin like growth factor I), to the final composition, may also effect the dosage. Progress can be monitored by periodic assessment of tissue/bone growth and/or repair, for example, X-rays, histomorphometric determinations and tetracycline labeling. 7.7. EFFECTIVE DOSAGE

[0242] Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount effective to prevent development of or to alleviate the existing symptoms of the subject being treated. Determination of the effective amounts is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. For any compound used in the method of the invention, the therapeutically effective dose can be estimated initially from appropriate in vitro assays. Such information can be used to more accurately determine useful doses in humans.

[0243] A therapeutically effective dose refers to that amount of the compound that results in amelioration of symptoms or a prolongation of survival in a patient. Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD₅₀ and ED₅₀. Compounds which exhibit high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED₅₀ with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. See, e.g., Fingl et al., 1975, in “The Pharmacological Basis of Therapeutics”, Ch. 1 p. 1. Dosage amount and interval may be adjusted individually to provide plasma levels of the active agent which are sufficient to maintain the desired effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.

[0244] Dosage intervals can also be determined using MEC value. Compounds should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

[0245] An exemplary dosage regimen for the human polypeptides of the invention will be in the range of about 0.01 to 100 mg/kg of body weight daily, with the preferred dose being about 0.1 to 25 mg/kg of patient body weight daily, varying in adults and children. Dosing may be once daily, or equivalent doses may be delivered at longer or shorter intervals.

[0246] The amount of composition administered will, of course, be dependent on the subject being treated, on the subject's age and weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.

7.8. PACKAGING

[0247] The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

8. ANTIBODIES

[0248] Another aspect of the invention is an antibody that specifically binds the apolipoprotein, lipase, or lipoprotein receptor polypeptide of the invention. Such antibodies include monoclonal and polyclonal antibodies, single chain antibodies, chimeric antibodies, bifunctional/bispecific antibodies, humanized antibodies, human antibodies, and complementary determining region (CDR)-grafted antibodies, including compounds which include CDR and/or antigen-binding sequences, which specifically recognize a polypeptide of the invention. Preferred antibodies of the invention are human antibodies which are produced and identified according to methods described in WO93/11236, published Jun. 20, 1993, which is incorporated herein by reference in its entirety. Antibody fragments, including Fab, Fab′, F(ab′)₂, and F_(v), are also provided by the invention. The term “specific for” indicates that the variable regions of the antibodies of the invention recognize and bind CG122, CG179, CG95, CG121, CG162, CG27, CG153 or CG168 polypeptides exclusively (i.e., able to distinguish a CG122 or CG179 polypeptide from other apolipoprotein polypeptides; CG95, CG121 or CG162 polypeptide from other lipase polypeptide; CG27, CG153 or CG168 polypeptide from other lipoprotein receptor polypeptide, despite sequence identity, homology, or similarity found in the family of polypeptides), but may also interact with other proteins (for example, S. aureus protein A or other antibodies in ELISA techniques) through interactions with sequences outside the variable region of the antibodies, and in particular, in the constant region of the molecule. Screening assays to determine binding specificity of an antibody of the invention are well known and routinely practiced in the art. For a comprehensive discussion of such assays, see Harlow et al. (Eds), Antibodies A Laboratory Manual; Cold Spring Harbor Laboratory; Cold Spring Harbor, N.Y. (1988), Chapter 6. Antibodies that recognize and bind fragments of the CG122, CG179, CG95, CG121, CG162, CG27, CG153, or CG168 polypeptides of the invention are also contemplated, provided that the antibodies are first and foremost specific for, as defined above, CG122, CG179, CG95, CG121, CG162, CG27, CG153 or CG168 polypeptides. As with antibodies that are specific for full length apolipoprotein polypeptides, antibodies of the invention that recognize CG122 or CG179 are those which can distinguish CG122 or CG179 polypeptides from the family of apolipoprotein polypeptides despite inherent sequence identity, homology, or similarity found in the family of proteins. As with antibodies that are specific for full length lipase polypeptides, antibodies of the invention that recognize CG95, CG121 or CG162 are those which can distinguish CG95, CG121 or CG162 polypeptides from the family of lipase polypeptides despite inherent sequence identity, homology, or similarity found in the family of proteins. As with antibodies that are specific for full length lipoprotein receptor polypeptides, antibodies of the invention that recognize CG27, CG153 or CG168 are those which can distinguish CG27, CG153 or CG168 polypeptides from the family of lipoprotein receptor polypeptides despite inherent sequence identity, homology, or similarity found in the family of proteins. Antibodies of the invention can be produced using any method well known and routinely practiced in the art.

[0249] Non-human antibodies may be humanized by any methods known in the art. In one method, the non-human CDRs are inserted into a human antibody or consensus antibody framework sequence. Further changes can then be introduced into the antibody framework to modulate affinity or immunogenicity.

[0250] Antibodies of the invention are useful for, for example, therapeutic purposes (by modulating activity of a polypeptide of the invention), diagnostic purposes to detect or quantitate a polypeptide of the invention, as well as purification of a polypeptide of the invention. Kits comprising an antibody of the invention for any of the purposes described herein are also comprehended. In general, a kit of the invention also includes a control antigen for which the antibody is immunospecific. The invention further provides a hybridoma that produces an antibody according to the invention. Antibodies of the invention are useful for detection and/or purification of the polypeptides of the invention.

[0251] Proteins of the invention may also be used to immunize animals to obtain polyclonal and monoclonal antibodies which specifically react with the protein. Such antibodies may be obtained using either the entire protein or fragments thereof as an immunogen. The peptide immunogens additionally may contain a cysteine residue at the carboxyl terminus, and are conjugated to a hapten such as keyhole limpet hemocyanin (KLH). Methods for synthesizing such peptides are known in the art, for example, as in R. P. Merrifield, J. Amer. Chem. Soc. 85, 2149-2154 (1963); J. L. Krstenansky, et al., FEBS Lett. 211, 10 (1987). Monoclonal antibodies binding to the protein of the invention may be useful diagnostic agents for the immunodetection of the protein. Neutralizing monoclonal antibodies binding to the protein may also be useful therapeutics for both conditions associated with the protein and also in the treatment of some forms of cancer where abnormal expression of the protein is involved. In the case of cancerous cells or leukemic cells, neutralizing monoclonal antibodies against the protein may be useful in detecting and preventing the metastatic spread of the cancerous cells, which may be mediated by the protein. In general, techniques for preparing polyclonal and monoclonal antibodies as well as hybridomas capable of producing the desired antibody are well known in the art (Campbell, A.M., Monoclonal Antibodies Technology: Laboratory Techniques in Biochemistry and Molecular Biology, Elsevier Science Publishers, Amsterdam, The Netherlands (1984); St. Groth et al., J. Immunol. 35:1-21 (1990); Kohler and Milstein, Nature 256:495-497 (1975)), the trioma technique, the human B-cell hybridoma technique (Kozbor et al., Immunology Today 4:72 (1983); Cole et al., in Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc. (1985), pp. 77-96).

[0252] Any animal (mouse, rabbit, etc.) which is known to produce antibodies can be immunized with a peptide or polypeptide of the invention. Methods for immunization are well known in the art. Such methods include subcutaneous or intraperitoneal injection of the polypeptide. One skilled in the art will recognize that the amount of the protein encoded by the ORF of the present invention used for immunization will vary based on the animal which is immunized, the antigenicity of the peptide and the site of injection. The protein that is used as an immunogen may be modified or administered in an adjuvant in order to increase the protein's antigenicity. Methods of increasing the antigenicity of a protein are well known in the art and include, but are not limited to, coupling the antigen with a heterologous protein (such as globulin or β-galactosidase) or through the inclusion of an adjuvant during immunization.

[0253] For monoclonal antibodies, spleen cells from the immunized animals are removed, fused with myeloma cells, such as SP2/0-Ag14 myeloma cells, and allowed to become monoclonal antibody producing hybridoma cells. Any one of a number of methods well known in the art can be used to identify the hybridoma cell which produces an antibody with the desired characteristics. These include screening the hybridomas with an ELISA assay, western blot analysis, or radioimmunoassay (Lutz et al., Exp. Cell Research. 175:109-124 (1988)). Hybridomas secreting the desired antibodies are cloned and the class and subclass is determined using procedures known in the art (Campbell, A.M., Monoclonal Antibody Technology: Laboratory Techniques in Biochemistry and Molecular Biology, Elsevier Science Publishers, Amsterdam, The Netherlands (1984)). Techniques described for the production of single chain antibodies (U.S. Pat. No. 4,946,778) can be adapted to produce single chain antibodies to proteins of the present invention.

[0254] For polyclonal antibodies, antibody containing antiserum is isolated from the immunized animal and is screened for the presence of antibodies with the desired specificity using one of the above-described procedures. The present invention further provides the above-described antibodies in delectably labeled form. Antibodies can be delectably labeled through the use of radioisotopes, affinity labels (such as biotin, avidin, etc.), enzymatic labels (such as horseradish peroxidase, alkaline phosphatase, etc.) fluorescent labels (such as FITC or rhodamine, etc.), paramagnetic atoms, etc. Procedures for accomplishing such labeling are well-known in the art, for example, see (Sternberger, L.A. et al., J. Histochem. Cytochem. 18:315 (1970); Bayer, E.A. et al., Meth. Enzym. 62:308 (1979); Engval, E. et al., Immunol. 109:129 (1972); Goding, J.W. J. Immunol. Meth. 13:215 (1976)).

[0255] The labeled antibodies of the present invention can be used for in vitro, in vivo, and in situ assays to identify cells or tissues in which a fragment of the polypeptide of interest is expressed. The antibodies may also be used directly in therapies or other diagnostics. The present invention further provides the above-described antibodies immobilized on a solid support. Examples of such solid supports include plastics such as polycarbonate, complex carbohydrates such as agarose and Sepharose®, acrylic resins and such as polyacrylamide and latex beads. Techniques for coupling antibodies to such solid supports are well known in the art (Weir, D.M. et al., “Handbook of Experimental Immunology” 4th Ed., Blackwell Scientific Publications, Oxford, England, Chapter 10 (1986); Jacoby, W.D. et al., Meth. Enzym. 34 Academic Press, N.Y. (1974)). The immobilized antibodies of the present invention can be used for in vitro, in vivo, and in situ assays as well as for immuno-affinity purification of the proteins of the present invention.

9. COMPUTER READABLE SEQUENCES

[0256] In one application of this embodiment, a nucleotide sequence of the present invention can be recorded on computer readable media. As used herein, “computer readable media” refers to any medium which can be read and accessed directly by a computer. Such media include, but are not limited to: magnetic storage media, such as floppy discs, hard disc storage medium, and magnetic tape; optical storage media such as CD-ROM; electrical storage media such as RAM and ROM; and hybrids of these categories such as magnetic/optical storage media. A skilled artisan can readily appreciate how any of the presently known computer readable mediums can be used to create a manufacture comprising computer readable medium having recorded thereon a nucleotide sequence of the present invention. As used herein, “recorded” refers to a process for storing information on computer readable medium. A skilled artisan can readily adopt any of the presently known methods for recording information on computer readable medium to generate manufactures comprising the nucleotide sequence information of the present invention.

[0257] A variety of data storage structures are available to a skilled artisan for creating a computer readable medium having recorded thereon a nucleotide sequence of the present invention. The choice of the data storage structure will generally be based on the means chosen to access the stored information. In addition, a variety of data processor programs and formats can be used to store the nucleotide sequence information of the present invention on computer readable medium. The sequence information can be represented in a word processing text file, formatted in commercially-available software such as WordPerfect and Microsoft Word, or represented in the form of an ASCII file, stored in a database application, such as DB2, Sybase, Oracle, or the like. A skilled artisan can readily adapt any number of data processor structuring formats (e.g. text file or database) in order to obtain computer readable medium having recorded thereon the nucleotide sequence information of the present invention. By providing the nucleotide sequence of SEQ ID NO: 1, 3, 5, 7, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42 or 44; or a representative fragment thereof; or a nucleotide sequence at least 99.9% identical to SEQ ID NO: 1, 3, 5, 7, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42 or 44 in computer readable form, a skilled artisan can routinely access the sequence information for a variety of purposes. Computer software is publicly available which allows a skilled artisan to access sequence information provided in a computer readable medium. The examples which follow demonstrate how software which implements the BLAST (Altschul et al., J. Mol. Biol. 215:403-410 (1990)) and BLAZE (Brutlag et al., Comp. Chem. 17:203-207 (1993)) search algorithms on a Sybase system is used to identify open reading frames (OREs) within a nucleic acid sequence. Such ORFs may be protein encoding fragments and may be useful in producing commercially important proteins such as enzymes used in fermentation reactions and in the production of commercially useful metabolites.

[0258] As used herein, “a computer-based system” refers to the hardware means, software means, and data storage means used to analyze the nucleotide sequence information of the present invention. The minimum hardware means of the computer-based systems of the present invention comprises a central processing unit (CPU), input means, output means, and data storage means. A skilled artisan can readily appreciate that any one of the currently available computer-based systems are suitable for use in the present invention. As stated above, the computer-based systems of the present invention comprise a data storage means having stored therein a nucleotide sequence of the present invention and the necessary hardware means and software means for supporting and implementing a search means. As used herein, “data storage means” refers to memory which can store nucleotide sequence information of the present invention, or a memory access means which can access manufactures having recorded thereon the nucleotide sequence information of the present invention.

[0259] As used herein, “search means” refers to one or more programs which are implemented on the computer-based system to compare a target sequence or target structural motif with the sequence information stored within the data storage means. Search means are used to identify fragments or regions of a known sequence which match a particular target sequence or target motif. A variety of known algorithms are disclosed publicly and a variety of commercially available software for conducting search means are and can be used in the computer-based systems of the present invention. Examples of such software includes, but is not limited to, MacPattern (EMBL), BLASTN and BLASTA (NPOLYPEPTIDEIA). A skilled artisan can readily recognize that any one of the available algorithms or implementing software packages for conducting homology searches can be adapted for use in the present computer-based systems. As used herein, a “target sequence” can be any nucleic acid or amino acid sequence of six or more nucleotides or two or more amino acids. A skilled artisan can readily recognize that the longer a target sequence is, the less likely a target sequence will be present as a random occurrence in the database. The most preferred sequence length of a target sequence is from about 10 to 100 amino acids or from about 30 to 300 nucleotide residues. However, it is well recognized that searches for commercially important fragments, such as sequence fragments involved in gene expression and protein processing, may be of shorter length.

[0260] As used herein, “a target structural motif,” or “target motif,” refers to any rationally selected sequence or combination of sequences in which the sequence(s) are chosen based on a three-dimensional configuration which is formed upon the folding of the target motif. There are a variety of target motifs known in the art. Protein target motifs include, but are not limited to, enzyme active sites and signal sequences. Nucleic acid target motifs include, but are not limited to, promoter sequences, hairpin structures and inducible expression elements (protein binding sequences).

10. TRIPLE HELIX FORMATION

[0261] In addition, gene expression can be controlled through triple helix formation or antisense DNA or RNA, both of which methods are based on the binding of a polynucleotide sequence to DNA or RNA. Polynucleotides suitable for use in these methods are usually 20 to 40 bases in length and are designed to be complementary to a region of the gene involved in transcription (triple helix - see Lee et al., Nucl. Acids Res. 6:3073 (1979); Cooney et al., Science 15241:456 (1988); and Dervan et al., Science 251:1360 (1991)) or to the mRNA itself (antisense - Olmno, J. Neurochem. 56:560 (1991); Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression, CRC Press, Boca Raton, Fla. (1988)). Triple helix- formation optimally results in a shut-off of RNA transcription from DNA, while antisense RNA hybridization blocks translation of an mRNA molecule into polypeptide. Both techniques have been demonstrated to be effective in model systems. Information contained in the sequences of the present invention is necessary for the design of an antisense or triple helix oligonucleotide.

11. DIAGNOSTIC ASSAYS AND KITS

[0262] The present invention further provides methods to identify the presence or expression of one of the ORFs of the present invention, or homolog thereof, in a test sample, using a nucleic acid probe or antibodies of the present invention, optionally conjugated or otherwise associated with a suitable label.

[0263] In general, methods for detecting a polynucleotide of the invention can comprise contacting a sample with a compound that binds to and forms a complex with the polypeptide for a period sufficient to form the complex, and detecting the complex, so that if a complex is detected, a polypeptide of the invention is detected in the sample. In detail, such methods comprise incubating a test sample with one or more of the antibodies or one or more of nucleic acid probes of the present invention and assaying for binding of the nucleic acid probes or antibodies to components within the test sample.

[0264] Conditions for incubating a nucleic acid probe or antibody with a test sample vary. Incubation conditions depend on the format employed in the assay, the detection methods employed, and the type and nature of the nucleic acid probe or antibody used in the assay. One skilled in the art will recognize that any one of the commonly available hybridization, amplification or immunological assay formats can readily be adapted to employ the nucleic acid probes or antibodies of the present invention. Examples of such assays can be found in Chard, T., An Introduction to Radioimmunoassay and Related Techniques, Elsevier Science Publishers, Amsterdam, The Netherlands (1986); Bullock, G. R. et al., Techniques in Immunocytochemistry, Academic Press, Orlando, Fla. Vol. 1 (1982), Vol. 2 (1983), Vol. 3 (1985); Tijssen, P., Practice and Theory of immunoassays: Laboratory Techniques in Biochemistry and Molecular Biology, Elsevier Science Publishers, Amsterdam, The Netherlands (1985). The test samples of the present invention include cells, protein or membrane extracts of cells, or biological fluids such as sputum, blood, serum, plasma, or urine. The test sample used in the above-described method will vary based on the assay format, nature of the detection method and the tissues, cells or extracts used as the sample to be assayed. Methods for preparing protein extracts or membrane extracts of cells are well known in the art and can be readily be adapted in order to obtain a sample which is compatible with the system utilized.

[0265] In another embodiment of the present invention, kits are provided which contain the necessary reagents to carry out the assays of the present invention. Specifically, the invention provides a compartment kit to receive, in close confinement, one or more containers which comprises: (a) a first container comprising one of the probes or antibodies of the present invention; and (b) one or more other containers comprising one or more of the following: wash reagents, reagents capable of detecting presence of a bound probe or antibody.

[0266] In detail, a compartment kit includes any kit in which reagents are contained in separate containers. Such containers include small glass containers, plastic containers or strips of plastic or paper. Such containers allows one to efficiently transfer reagents from one compartment to another compartment such that the samples and reagents are not cross-contaminated, and the agents or sohltions of each container can be added in a quantitative fashion from one compartment to another. Such containers will include a container which will accept the test sample, a container which contains the antibodies used in the assay, containers which contain wash reagents (such as phosphate buffered saline, Tris-buffers, etc.), and containers which contain the reagents used to detect the bound antibody or probe. Types of detection reagents include labeled nucleic acid probes, labeled secondary antibodies, or in the alternative, if the primary antibody is labeled, the enzymatic; or antibody binding reagents which are capable of reacting with the labeled antibody. One skilled in the art will readily recognize that the disclosed probes and antibodies of the present invention can be readily incorporated into one of the established kit formats which are well known in the art.

12. MEDICAL IMAGING

[0267] The novel polypeptides of the invention are useful in medical imaging, e.g., imaging the site of infection, inflammation, and other sites expressing CG122 or CG179 apolipoprotein molecules; CG95, CG121 or CG162 lipase molecules; or CG27, CG153 or CG168 lipoprotein receptor molecules. See, e.g., Kunkel et al., U.S. Pat. No. 5,413,778. Such methods involve chemical attachment of a labeling or imaging agent, administration of the labeled polypeptide to a subject in a pharmaceutically acceptable carrier, and imaging the labeled polypeptide in vivo at the target site.

13. SCREENING ASSAYS

[0268] Using the isolated proteins and polynucleotides of the invention, the present invention further provides methods of obtaining and identifying agents which bind to a polypeptide encoded by the ORF from a polynucleotide of the invention to a specific domain of the polypeptide encoded by a polypeptide of the invention. In detail, said method comprises the steps of:

[0269] (a) contacting an agent with an isolated protein encoded by an ORF of the present invention, or nucleic acid of the invention; and

[0270] (b) determining whether the agent binds to said protein or said nucleic acid.

[0271] In general, therefore, such methods for identifying compounds that bind to a polynucleotide of the invention can comprise contacting a compound with a polynucleotide of the invention for a time sufficient to form a polynucleotide/compound complex, and detecting the complex, so that if a polynucleotide/compound complex is detected, a compound that binds to a polynucleotide of the invention is identified.

[0272] Likewise, in general, therefore, such methods for identifying compounds that bind to a polypeptide of the invention can comprise contacting a compound with a polypeptide of the invention for a time sufficient to form a polypeptide/compound complex, and detecting the complex, so that if a polypeptide/compound complex is detected, a compound that binds to a polynucleotide of the invention is identified.

[0273] Methods for identifying compounds that bind to a polypeptide of the invention can also comprise contacting a compound with a polypeptide of the invention in a cell for a time sufficient to form a polypeptide/compound complex, wherein the complex drives expression of a receptor gene sequence in the cell, and detecting the complex by detecting reporter gene sequence expression, so that if a polypeptide/compound complex is detected, a compound that binds a polypeptide of the invention is identified.

[0274] Compounds identified via such methods can include compounds which modulate the activity of a polypeptide of the invention (that is, increase or decrease its activity, relative to activity observed in the absence of the compound). Alternatively, compounds identified via such methods can include compounds which modulate the expression of a polynucleotide of the invention (that is, increase or decrease expression relative to expression levels observed in the absence of the compound). Compounds, such as compounds identified via the methods of the invention, can be tested using standard assays well known to those of skill in the art for their ability to modulate activity/expression.

[0275] The agents screened in the above assay can be, but are not limited to, peptides, carbohydrates, vitamin derivatives, or other pharmaceutical agents. The agents can be selected and screened at random or rationally selected or designed using protein modeling techniques.

[0276] For random screening, agents such as peptides, carbohydrates, pharmaceutical agents and the like are selected at random and are assayed for their ability to bind to a protein encoded by an ORF of the present invention. Alternatively, agents may be rationally selected or designed. As used herein, an agent is said to be “rationally selected or designed” when the agent is chosen based on the configuration of the particular protein. For example, one skilled in the art can readily adapt currently available procedures to generate peptides, pharmaceutical agents and the like capable of binding to a specific peptide sequence in order to generate rationally designed antipeptide peptides, for example see Hurby et al., Application of Synthetic Peptides: Antisense Peptides,″In Synthetic Peptides, A User's Guide, W. H. Freeman, NY (1992), pp. 289-307, and Kaspczak et al., Biochemistry 28:9230-8 (1989), or pharmaceutical agents, or the like.

[0277] In addition to the foregoing, one class of agents of the present invention, as broadly described, can be used to control gene expression through binding to one of the ORFs or EMFs of the present invention. As described above, such agents can be randomly screened or rationally designed/selected. Targeting the ORF or EMF allows a skilled artisan to design sequence specific or element specific agents, modulating the expression of either a single ORF or multiple ORFs which rely on the same EMF for expression control. One class of DNA binding agents are agents which contain base residues which hybridize or form a triple helix formation by binding to DNA or RNA. Such agents can be based on the classic phosphodiester, ribonucleic acid backbone, or can be a variety of sulfhydryl or polymeric derivatives which have base attachment capacity.

[0278] Agents suitable for use in these methods usually contain 20 to 40 bases and are designed to be complementary to a region of the gene involved in transcription (triple helix—see Lee et al., Nucl. Acids Res. 6:3073 (1979); Cooney et al., Science 241:456 (1988); and Dervan et al., Science 251:1360 (1991)) or to the mRNA itself (antisense—Okano, J. Neurocheni. 56:560 (1991); Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression, CRC Press, Boca Raton, Fla. (1988)). Triple helix-formation optimally results in a shut-off of RNA transcription from DNA, while antisense RNA hybridization blocks translation of an mRNA molecule into polypeptide. Both techniques have been demonstrated to be effective in model systems. Information contained in the sequences of the present invention is necessary for the design of an antisense or triple helix oligonucleotide and other DNA binding agents. Agents which bind to a protein encoded by one of the ORFs of the present invention can be used as a diagnostic agent, in the control of bacterial infection by modulating the activity of the protein encoded by the ORF. Agents which bind to a protein encoded by one of the ORFs of the present invention can be formulated using known techniques to generate a pharmaceutical composition.

14. USE OF NUCLEIC ACIDS AS PROBES

[0279] Another aspect of the subject invention is to provide for polypeptide-specific nucleic acid hybridization probes capable of hybridizing with naturally occurring nucleotide sequences. The hybridization probes of the subject invention may be derived from the nucleotide sequence of the SEQ ID NO: 1, 3, 5, 7, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42 or 44. Because the corresponding gene is only, expressed in a limited number of tissues, a hybridization probe derived from SEQ ID NO: 1, 3, 5, 7, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42 or 44 can be used as an indicator of the presence of RNA of cell type of such a tissue in a sample.

[0280] Any suitable hybridization technique can be employed, such as, for example, in situ hybridization. PCR as described U.S. Pat. Nos. 4,683,195 and 4,965,188 provides additional uses for oligonucleotides based upon the nucleotide, sequences. Such probes used in PCR may be of recombinant origin, may be chemically synthesized, or a mixture of both. The probe will comprise a discrete nucleotide sequence for the detection of identical sequences or a degenerate pool of possible sequences for identification of closely related genomic sequences.

[0281] Other means for producing specific hybridization probes for nucleic acids include the cloning of nucleic acid sequences into vectors for the production of mRNA probes. Such vectors are known in the art and are commercially available and may be used to synthesize RNA probes in vitro by means of the addition of the appropriate RNA polymerase as T7 or SP6 RNA polymerase and the appropriate radioactively labeled nucleotides. The nucleotide sequences may be used to construct hybridization probes for mapping their respective genomic sequences. The nucleotide sequence provided herein may be mapped to a chromosome or specific regions of a chromosome using well known genetic and/or chromosomal mapping techniques. These techniques include in situ hybridization, linkage analysis against known chromosomal markers, hybridization screening with libraries or flow-sorted chromosomal preparations specific to known chromosomes, and the like. The technique of fluorescent in situ hybridization of chromosome spreads has been described, among other places, in Verma et al (1988) Human Chromosomes: A Manual of Basic Techniques, Pergamon Press, New York N.Y.

[0282] Fluorescent in situ hybridization of chromosomal preparations and other physical chromosome mapping techniques may be correlated with additional genetic map data. Examples of genetic map data can be found in the 1994 Genome Issue of Science (265:1981f). Correlation between the location of a nucleic acid on a physical chromosornal map and a specific disease (or predisposition to a specific disease) may help delimit the region of DNA associated with that genetic disease. The nucleotide sequences of the subject invention may be used to detect differences in gene sequences between normal, carrier or affected individuals. The nucleotide sequence may be used to produce purified polypeptides using well known methods of recombinant DNA technology. Among the many publications that teach methods for the expression of genes after they have been isolated is Goeddel (1990) Gene Expression Technology, Methods and Enzymology, Vol 185, Academic Press, San Diego. Polypeptides may be expressed in a variety of host cells, either prokaryotic or eukaryotic. Host cells may be from the same species from which a particular polypeptide nucleotide sequence was isolated or from a different species. Advantages of producing polypeptides by recombinant DNA technology include obtaining adequate amounts of the protein for purification and the availability of simplified purification procedures.

[0283] Each sequence so-obtained was compared to sequences in GenBank using a search algorithm developed by Applied Biosystems and incorporated into the INHERIT™ 670 Sequence Analysis System. In this algorithm, Pattern Specification Language (developed by TRW Inc., Los Angeles, Calif.) was used to determine regions of homology. The three parameters that determine how the sequence comparisons run were window size, window offset, and error tolerance. Using a combination of these three parameters, the DNA database was searched for sequences containing regions of homology to the query sequence, and the appropriate sequences were scored with an initial value. Subsequently, these homologous regions were examined using dot matrix homology plots to distinguish regions of homology from chance matches. Smith-Waterman alignments were used to display the results of the homology search. Peptide and protein sequence homologies were ascertained using the INHERIT™ 670 Sequence Analysis System in a way similar to that used in DNA sequence homologies. Pattern Specification Language and parameter windows were used to search protein databases for sequences containing regions of homology that were scored with an initial value. Dot-matrix homology plots were examined to distinguish regions of significant homology from chance matches.

[0284] Alternatively, BLAST, which stands for Basic Local Alignment Search Tool, is used to search for local sequence alignments (Altschul SF (1993) J Mol Evol 36:290-300; Altschul, SF et al (1990) J Mol Biol 215:403-10). BLAST produces alignments of both nucleotide and amino acid sequences to determine sequence similarity. Because of the local nature of the alignments, BLAST is especially useful in determining exact matches or in identifying homologs. Whereas it is ideal for matches which do not contain gaps, it is inappropriate for performing motif-style searching. The fundamental unit of BLAST algorithm output is the High-scoring Segment Pair (HSP). An HSP consists of two sequence fragments of arbitrary but equal lengths whose alignment is locally maximal and for which the alignment score meets or exceeds a threshold or cutoff score set by the user. The BLAST approach is to look for HSPs between a query sequence and a database sequence, to evaluate the statistical significance of any matches found, and to report only those matches which satisfy the user-selected threshold of significance. The parameter E establishes the statistically significant threshold for reporting database sequence matches. E is interpreted as the upper bound of the expected frequency of chance occurrence of an HSP (or set of HSPs) within the context of the entire database search. Any database sequence whose match satisfies E is reported in the program output.

14.1Preparation of Sequencing Chips and Arrays

[0285] A basic example is using 6-mers attached to 50 micron surfaces to give a chip with dimensions of 3×3 mm which can be combined to give an array of 20×20 cm. Another example is using 9-mer oligonucleotides attached to 10×10 microns surface to create a 9—mer chip, with dimensions of 5×5 mm. 4000 units of such chips may be used to create a 30×30 cm array. In an array in which 4,000 to 16,000 oligoclips are arranged into a squire array. A plate, or collection of tubes, as also depicted, may be packaged with the array as part of the sequencing kit.

[0286] The arrays may be separated physically from each other or by hydrophobic surfaces. One possible way to utilize the hydrophobic strip separation is to use technology such as the Iso-Grid Microbiology System produced by QA Laboratories, Toronto, Canada.

[0287] Hydrophobic grid membrane filters (HGMF) have been in use in analytical food microbiology for about a decade where they exhibit unique attractions of extended numerical range and automated counting of colonies. One commercially-available grid is ISO-GRID™ from QA Laboratories Ltd. (Toronto, Canada) which consists of a square (60×60 cm) of polysulfone polymer (Gelman Tuffryn HT-450, 0.46u pore size) on which is printed a black hydrophobic ink grid consisting of 1600 (40×40) square cells. HGMF have previously been inoculated with bacterial suspensions by vacuum filtration and incubated on the differential or selective media of choice.

[0288] Because the microbial growth is confined to grid cells of known position and size on the membrane, the HGMF functions more like an MPN apparatus than a conventional plate or membrane filter. Peterkin et. al. (1987) reported that these HGMFs can be used to propagate and store genomic libraries when used with a HGMF replicator. One such Instrument replicates growth from each of the 1600 cells of the ISO-GRID and enables many copies of the master HGMF to be made (Peterkin et al., 1987).

[0289] Sharpe et al. (1989) also used ISO-GRID HGMF form QA Laboratories and an automated HGMF counter (MI-100 Interpreter) and RP-100 Replicator. They reported a technique for maintaining and screening many microbial cultures.

[0290] Peterkin and colleagues later described a method for screening DNA probes using the hydrophobic grid-membrane filter (Peterkin et al., 1989). These authors reported: methods for effective colony hybridization directly on HGMFs. Previously, poor results had been obtained due to the low DNA binding capacity of the epoxysulfone polymer on which the HGMFs are printed. However, Peterkin et al. (1989) reported that the binding of DNA to the surface of the membrane was improved by treating the replicated and incubated HGMF with polyethyleneimine, a polycation, prior to contact with DNA. Although this early work uses cellular DNA attachment, and has a different objective to the present, invention, the methodology described may be readily adapted for Format 3 SBH.

[0291] In order to identify useful sequences rapidly, Peterkin et al. (1989) used radiolabeled plasmid DNA from various clones and tested its specificity against the DNA on the prepared HGMFs. In this way, DNA from recombinant plasmids was rapidly screened by colony hybridization against 100 organisms on HGMF replicates which can be easily and reproducibly prepared.

[0292] Manipulation with small (2-3 mm)chips, and parallel execution of thousands of the reactions. The solution of the invention is to keep the chips and the probes in the corresponding arrays. In one example, chips containing 250,000 9-mers are synthesized on a silicon wafer in the form of 8×8 mM plates (15 uM/oligonucleotide, Pease et al., 1994) arrayed in 8×12 format (96 chips) with a 1 mM groove in between. Probes are added either by multichannel pipette or pin array, one probe on one chip. To score all 4000 6-mers, 42 chip arrays have to be used, either using different ones, or by reusing one set of chip arrays several times.

[0293] In the above case, using the earlier nomenclature of the application, F=9; P=6; and F+P=15. Chips may have probes of formula BxNn, where x is a number of specified bases B; and n is a number of non-specified bases, so that x=4 to 10 and n=1 to 4. To achieve more efficient hybridization, and to avoid potential influence of any support oligonucleotides, the specified bases can be surrounded by unspecified bases, thus represented by a formula such as (N)nBx(N)m.

14.2 Preparation of Support Bound Oligonucleotides

[0294] Ohgonucleotides, i.e., small nucleic acid segments, may be readily prepared by, for example, directly synthesizing the oligonucleotide by chemical means, as is commonly practiced using an automated oligonucleotide synthesizer.

[0295] Support bound oligonucleotides may be prepared by any of the methods known to those of skill in the art using any suitable support such as glass, polystyrene or Teflon. One strategy is to precisely spot oligonucleotides synthesized by standard synthesizers. Immobilization can be achieved using passive adsorption (Inouye & Hondo, 1990); using UV light (Nagata et al, 1985; Dahlen et al, 1987; Morriey & Collins, 1989) or by covalent binding of base modified DNA (Keller et al., 1988; 1989); all references being specifically incorporated herein.

[0296] Another strategy that may be employed is the use of the strong biotin-streptavidin interaction as a linker. For example, Broude et al. (1994) describe the use of Biotinylated probes, although these are duplex probes, that are immobilized on streptavidin-coated magnetic beads. Streptavidin-coated beads may be purchased from Dynal, Oslo. Of course, this same linking chemistry is applicable to coating any surface with streptavidin. Biotinylated probes may be purchased from various sources, such as, e.g., Operon Technologies (Alameda, Calif.).

[0297] Nunc Laboratories (Naperville, Ill.) is also selling suitable material that could be used. Nunc Laboratories have developed a method by which DNA can be covalently bound to the microwell surface termed Covalink NH. CovaLink NH is a polystyrene surface grafted with secondary amino groups (>NH) that serve as bridge-heads for further covalent coupling. CovaLink Modules may be purchased from Nunc Laboratories. DNA molecules may be bound to CovaLink exclusively at the 5′-end by a phosphoramidate bond, allowing immobilization of more than 1 pmol of DNA (Rasmussen et al., 1991).

[0298] The use of CovaLink NH strips for covalent binding of DNA molecules at the 5′-end has been described (Rasmussen et al., 1991). In this technology, a phosphoramidate bond is employed (Chu et al., 1983). This is beneficial as immobilization using only a single covalent bond is preferred. The phosphoramidate bond joins the DNA to the CovaLink NH secondary amino groups that are positioned at the end of spacer arms covalently grafted onto the polystyrene surface through a 2 nm long spacer arm. To link an oligonucleotide to CovaLink NH via an phosphoramidate bond, the oligonucleotide terminus must have a 5′-end phosphate group. It is, perhaps, even possible for biotin to be covalently bound to CovaLink and then streptavidin used to bind the probes.

[0299] More specifically, the linkage method includes dissolving DNA in water (7.5 ng/ul) and denaturing for 10 min. at 95° C. and cooling on ice for 10 min. Ice-cold 0.1 M 1-methylimidazole, pH 7.0 (1-MeIm₇), is then added to a final concentration of 10 mM 1-MeIm₇. A ss DNA solution is then dispensed into CovaLink NH strips (75 ul/well) standing on ice.

[0300] Carbodiimide 0.2 M 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC), dissolved in 10 mM 1 -MeIm₇, is made fresh and 25 ul added per well. The strips are incubated for 5 hours at 50° C. After incubation the strips are washed using, e.g., Nunc-Immuno Wash; first the wells are washed 3 times, then they are soaked with washing solution for 5 min., and finally they are washed 3 times (where in the washing solution is 0.4 N NaOH, 0.25% SDS heated to 50° C.).

[0301] It is contemplated that a further suitable method for use with the present invention is that described in PCT Patent Application WO 90/03382 (Southern & Maskos), incorporated herein by reference. This method of preparing an oligonucleotide bound to a support involves attaching a nucleoside 3′-reagent through the phosphate group by a covalent phosphodiester link to aliphatic hydroxyl groups carried by the support. The oligonucleotide is then synthesized on the supported nucleoside and protecting groups removed from the synthetic oligonucleotide chain under standard conditions that do not cleave the oligonucleotide from the support. Suitable reagents include nucleoside phosphoramidite and nucleoside hydrogen phosphorate.

[0302] An on-chip strategy for the preparation of DNA probe for the preparation of DNA probe arrays may be employed. For example, addressable laser-activated photodeprotection may be employed in the chemical synthesis of oligoinucleotides directly on a glass surface, as described by Fodor et al. (1991), incorporated herein by reference. Probes may also be immobilized on nylon supports as described by Van Ness et al. (1991); or linked to Teflon using the method of Duncan & Cavalier (1988); all references being specifically incorporated herein.

[0303] To link an oligonucleotide to a nylon support, as described by Van Ness et al (1991), requires activation of the nylon surface via alkylation and selective activation of the 5′-amine of oligonucleotides with cyanuric chloride.

[0304] One particular way to prepare support bound oligonucleotides is to utilize the light-generated synthesis described by Pease et al., (1994, incorporated herein by reference). These authors used current photolithographic techniques to generate arrays of immobilized oligonucleotide probes (DNA chips). These methods, in which light is used to direct the synthesis of oligonucleotide probes in high-density, miniaturized arrays, utilize photolabile 5′-protected N-acyl-deoxynucleoside phosphoramidites, surface linker chemistry and versatile combinatorial synthesis strategies. A matrix of 256 spatially defined oligonucleotide probes may be generated in this manner and then used in the advantageous Format 3 sequencing, as described herein.

14.3 Preparation of Nucleic Acid Fragments

[0305] The nucleic acids to be sequenced may be obtained from any appropriate source, such as cDNAs, genomic DNA, chromosomal DNA, microdissected chromosome bands, cosmid or YAC inserts, and RNA, including mRNA without any amplification steps. For example, Sambrook et al. (1989) describes three protocols for the isolation of high molecular weight DNA from mammalian cells (p. 9.14-9.23).

[0306] DNA fragments may be prepared as clones in M13, plasmid or lambda vectors and/or prepared directly from genomic DNA or cDNA by PCR or other amplification methods. Samples may be prepared or dispensed in multiwell plates About 100-1000 ng of DNA samples may be prepared in 2-500 ml of final volume.

[0307] The nucleic acids would then be fragmented by any of the methods known to those of skill in the art including, for example, using restriction enzymes as described at 9.24-9.28 of Sambrook et al. (1989), shearing by ultrasound and NaOH treatment.

[0308] Low pressure shearing is also appropriate, as described by Schriefer et al. (1990, incorporated herein by reference). In this method, DNA samples are passed through a small French pressure cell at a variety of low to intermediate pressures. A lever device allows controlled application of low to intermediate pressures to the cell. The results of these studies indicate that low-pressure shearing is a useful alternative to sonic and enzymatic DNA fragmentation methods.

[0309] One particularly suitable way for fragmenting DNA is contemplated to be that using the two base recognition endonuclease, CviJI, described by Fitzgerald et al. (1992). These authors described an approach for the rapid fragmentation and fractionation of DNA into particular sizes that they contemplated to be suitable for shotgun cloning and sequencing. The present inventor envisions that this will also be particularly useful for generating random, but relatively small, fragments of DNA for use in the present sequencing technology.

[0310] The restriction endonuclease CviJI normally cleaves the recognition sequence PuGCPy between the G and C to leave blunt ends. Atypical reaction conditions, which alter the specificity of this enzyme (CviJI**), yield a quasi-random distribution of DNA fragments form the small molecule pUC19 (2688 base pairs). Fitzgerald et al. (1992) quantitatively evaluated the randomness of this fragmentation strategy, using a CviJI** digest of pUC 19 that was size fractionated by a rapid gel filtration method and directly ligated, without end repair, to a lac Z minus M13 cloning vector. Sequence analysis of 76 clones showed that CviJI** restricts pyGCPy and PuGCPu, in addition to PuGCPy sites, and that new sequence data is accumulated at a rate consistent with random fragmentation.

[0311] As reported in the literature, advantages of this approach compared to sonication and agarose gel fractionation include: smaller amounts of DNA are required (0.2-0.5 ug instead of 2-5 ug); and fewer steps are involved (no preligation, end repair, chemical extraction, or agarose gel electrophoresis and elution are needed). These advantages are also proposed to be of use when preparing DNA for sequencing by Format 3.

[0312] Irrespective of the manner in which the nucleic acid fragments are obtained or prepared, it is important to denature the DNA to give single stranded pieces available for hybridization. This is achieved by incubating the DNA solution for 2-5 minutes at 80-90° C. The solution is then cooled quickly to 2° C. to prevent renaturation of the DNA fragments before they are contacted with the chip. Phosphate groups must also be removed from genomic DNA by methods known in the art.

14.4 Preparation of DNA Arrays

[0313] Arrays may be prepared by spotting DNA samples on a support such as a nylon membrane. Spotting may be performed by using arrays of metal pins (the positions of which correspond to an array of wells in a microtiter plate) to repeated by transfer of about 20 nl of a DNA solution to a nylon membrane. By offset printing, a density of dots higher than the density of the wells is achieved. One to 25 dots may be accommodated in 1 mm², depending on the type of label used. By avoiding spotting in some preselected number of rows and columns, separate subsets (subarrays) may be formed. Samples in one subarray may be the same genomic segment of DNA (or the same gene) from different individuals, or may be different, overlapped genomic clones. Each of the subarrays may represent replica spotting of the same samples. In one example, a selected gene segment may be amplified from 64 patients. For each patient, the amplified gene segment may be in one 96-well plate (all 96 wells containing the same sample). A plate for each of the 64 patients is prepared. By using a 96-pin device, all samples may be spotted on one 8×12 cm membrane. Subarrays may contain 64 samples, one from each patient. Where the 96 subarrays are identical, the dot span may be 1 mm² and there may be a 1 mm space between subarrays.

[0314] Another approach is to use membranes or plates (available from NUNC, Naperville, Ill.) which may be partitioned by physical spacers e.g. a plastic grid molded over the membrane, the grid being similar to the sort of membrane applied to the bottom of multiwell plates, or hydrophobic strips. A fixed physical spacer is not preferred for imaging by exposure to flat phosphor-storage screens or x-ray films.

14.5 Sequence Comparisons

[0315] Preferred identity and/or similarity are designed to give the largest match between the sequences tested. Methods to determine identity and similarity are codified in publicly available computer programs including, but are not limited to, the GCG program package, including GAP (Devereux, J., et al., Nucleic Acids Research 12(1):387 (1984); Genetics Computer Group, University of Wisconsin, Madison, Wis.), BLASTP, BLASTN, BLASTX, and FASTA (Atschul, S.F. et al., J. Molec. Biol. 215:403-410 (1990). The BLAST X program is publicly available from the National Center for Biotechnology Information (NCBI) and other sources (BLAST Manual. Altschul, S., et al. NCB NLM NIH Bethesda, Md. 20894; Altschul, S., et al., J. Mol. Biol 215:403-410 (1990). The preferred computer program is FASTA version 3, specifically the FASTy program within the FASTA program package. Another preferred algorithm is the well known Smith Waterman algorithm which can also be used to determine identity.

[0316] Sequences can be compared to sequences in GenBank using a search algorithm developed by Applied Biosystems and incorporated into the INHERIT™ 670 Sequence Analysis System. In this algorithm, Pattern Specification Language (developed by TRW Inc., Los Angeles, Calif.) is used to determine regions of homology. The three parameters that determine how the sequence comparisons run are window size, window offset, and error tolerance. Using a combination of these three parameters, the DNA database can be searched for sequences containing regions of homology to the query sequence, and the appropriate sequences scored with an initial value. Subsequently, these homologous regions are examined using dot matrix homology plots to distinguish regions of homology from chance matches. Smith-Waterman alignments can be used to display the results of the homology search. Peptide and protein sequence homologies can be ascertained using the INHERIT™ 670 Sequence Analysis System in a way similar to that used in DNA sequence homologies. Pattern Specification Language and parameter windows are used to search protein databases for sequences containing regions of homology that were scored with an initial value. Dot-matrix homology plots can be examined to distinguish regions of significant homology from chance matches.

[0317] Alternatively, BLAST, which stands for Basic Local Alignment Search Tool, is used to search for local sequence alignments (Altschul SF (1993) J Mol Evol 36:290-300; Altschul, SF et al (1990) J Mol Biol 215:403-10). BLAST produces alignments of both nucleotide and amino acid sequences to determine sequence similarity. Because of the local nature of the alignments, BLAST is especially useful in determining exact matches or in identifying homologs. Whereas it is ideal for matches which do not contain gaps, it is inappropriate for performing motif-style searching. The fundamental unit of BLAST algorithm output is the High-scoring Segment Pair (HSP). An HSP consists of two sequence fragments of arbitrary but equal lengths whose alignment is locally maximal and for which the alignment score meets or exceeds a threshold or cutoff score set by the user. The BLAST approach is to look for HSPs between a query sequence and a database sequence, to evaluate the statistical significance of any matches found, and to report only those matches which satisfy the user-selected threshold of significance. The parameter E establishes the statistically significant threshold for reporting database sequence matches. E is interpreted as the upper bound of the expected frequency of chance occurrence of an HSP (or set of HSPs) within the context of the entire database search.

[0318] The present invention is illustrated in the following examples. Upon consideration of the present disclosure, one of skill in the art will appreciate that many other embodiments and variations may be made in the scope of the present invention. Accordingly, it is intended that the broader aspects of the present invention not be limited to the disclosure of the following examples.

EXAMPLE 1 Cloning of Apolipoprotein, Lipase, and Lipoprotein Receptor cDNAs

[0319] Novel nucleic acids were obtained from various cDNA libraries prepared from human MRNA purchased from Invitrogen, San Diego, Calif.) using standard PCR, sequencing by hybridization (SBH) sequence signature analysis and Sanger sequencing techniques. The inserts of the library were amplified with PCR using primers specific for pSport1 (GIBCO BRL, Grand Island, N.Y.) vector sequences which flank the inserts. These samples were spotted onto nylon membranes and hybridized with oligonucleotide probes to give sequence signatures. The clones were clustered into groups of similar or identical sequences, and single representative clones were selected from each group for gel sequencing. The 5′ sequence of the amplified inserts was then deduced using the reverse M13 sequencing primer in a typical Sanger sequencing protocol. PCR products were purified and subjected to flourescent dye terminator cycle sequencing. Single pass gel sequencing was done using a 377 Applied Biosystems (ABI) sequencer.

[0320] Sequence analysis identified a polynlcleotides encoding novel polypeptides designated CG122, CG179, CG95, CG121, CG162, CG27, CG153, and CG168. The 5′ sequence was determined as described in Example 2.

EXAMPLE 2 5′ RACE Extension of Genes

[0321] 5′ RACE reactions were performed using pairs of nested gene-specific primers (GSP) and vector primers (VP) in sequential PCR reactions on a panel of cDNA libraries. The cDNA libraries used for RACE were prepared from mRNA using a random-primed, 5′ capture method to enrich for the 5′ ends of genes (Carninci et al, Genomics, 37, 327-336, 1996) and cloned into the pSPORT vector (BRL Life Technologies) previously digested with NotI and SalI. The human mRNAs (Invitrogen) included message from adult brain, adult thymus, fetal muscle, fetal skin, fetal heart, fetal brain, fetal spleen, fetal liver, and fetal lung. In addition, adaptor-ligated cDNA pools (Marathon cDNAs, Clontech) made from human fetal kidney, fetal brain and adult ovary mRNAs were used in the RACE experiments.

[0322] Generally, in the first reaction, a first GSP (T_(m)˜80° C.) and VP (T_(m)˜72° C.) are mixed in a 5:1 ratio. Touchdown PCR was carried out as follows: an initial incubation at 96° C. for one minute, followed by five cycles of 96° C. for 30 seconds and 72° C. for four minutes; five cycles of 96° C. for 30 seconds and 70° C. for four minutes; and 15 cycles of 96° C. for 30 seconds and 68° C. for four minutes. The products of the first reaction were diluted 1:20 and used as template for the second reaction. Second nested GSP and VP (both T_(m)˜60° C.) were mixed in a 1:1 ratio and PCR was carried out as follows: an initial incubation at 96° C. for one minute; and 30 cycles of 96° C. for 30 seconds, 55° C. for 30 seconds, and 72° C. for 90 seconds. This step was sometimes repeated with a third or more nested GSP and VP primer. Final RACE products were separated and identified using agarose gel electrophoresis. Selected fragments were subcloned into a TA cloning vector and the inserts were sequenced.

EXAMPLE 3 Tissue Expression Study

[0323] PCR Analysis

[0324] Gene expression of the polypeptides of the invention is analyzed using a semi-quantitative PCR-based technique. A panel of cDNA libraries derived from human tissue (from Clontech and Invitrogen) is screened with gene specific primers to examine the mRNA expression of the gene in human tissues and cell types. PCR assays (For example, 94° C. for 30 sec., 58° C. for 30 sec., 72° C. for 30 sec., for 30 cycles) are performed with 20 ng of cDNA derived from human tissues and cell lines and 10 picomoles of the appropriate gene-specific primers. The PCR product is identified through gel electrophoresis. Amplified products are separated on an agarose gel, transferred and chemically linkled to a nylon filter. The filter is then hybridized with a radioactively labeled (³³Pα-dCTP) double-stranded probe generated from the full-length sequence using a Klenow polyinerase, random prime method. The filters are washed (high stringency) and used to expose a phosphorimaging screen for several hours. Bands of the appropriate size indicate the presence of cDNA sequences in a specific library, and thus mRNA expression in the corresponding cell type or tissue.

[0325] Expression analysis can also be conducted using Northern blot techniques.

EXAMPLE 4 Chromosomal Localization Study

[0326] Chromosome mapping technologies allow investigators to link genes to specific regions of chromosomes. Chromosomal mapping is performed using the NIGMS human/rodent somatic cell hybrid mapping panel as described by Drwinga, H. L. et al., Genomics, 16, 311-314, 1993 (human/rodent somatic cell hybrid mapping panel #2 purchased from the Coriell Institute for Medical Research, Camden, N.J.). 60 ng of DNA from each sample in the panel is used as template, and 10 picomoles of the appropriate gene-specific oligonucleotides are used as primers in a PCR assay (for example, 94° C. for 30 sec., 58° C. for 30 sec., 72° C. for 30 sec., for 30 cycles). PCR products were analyzed by gel electrophoresis. The genomic PCR product is detected in a human/rodent somatic cell hybrid DNA containing a specific human chromosome.

EXAMPLE 5 Expression of Polypeptides in E. coli

[0327] A nucleic acid sequence of the invention is expressed in E. coli by subcloning the entire coding region into a prokalyotic expression vector. The expression vector (pQE16) used is from the QIAexpression® prokaryotic protein expression system (QIAGEN). The features of this vector that make it useful for protein expression include: an efficient promoter (phage T5) to drive transcription; expression control provided by the lac operator system, which can be induced by addition of IPTG (isopropyl-62 -D-thiogalactopyranoside), and an encoded His₆ tag. The latter is a stretch of 6 histidine amino acid residues which can bind very tightly to a nickel atom. The vector can be used to express a recombinant protein with a His₆ tag fused to its carboxyl terminus, allowing rapid and efficient purification using Ni-coupled affinity columns.

[0328] PCR is used to amplify the coding region which is then ligated into digested pQE16) vector. The ligation product is transformed by electroporation into electrocompetent E.coli cells (strain M15[pREP4] from QIAGEN), and the transformed cells are plated on ampicillin-containing plates. Colonies are screened for the correct insert in the proper orientation using a PCR reaction employing a gene-specific primer and a vector-specific primer. Positives are then sequenced to ensure correct orientation and sequence. To express cytokine receptor polypeptides, a colony containing a correct recombinant clone is inoculated into L-Broth containing 100 μg/ml of ampicillin, 25 μg/ml of kanamycin, and the culture was allowed to grow overnight at 37° C. The saturated culture is then diluted 20-fold in the same medium and allowed to grow to an optical density at 600 nm of 0.5. At this point, IPTG is added to a final concentration of 1 mM to induce protein expression. The culture is allowed to grow for 5 more hours, and then the cells are harvested by centrifugation at 3000×g for 15 minutes.

[0329] The resultant pellet is lysed using a mild, nonionic detergent in 20 mM Tris HCl (pH 7.5) (B-PERTM Reagent from Pierce), or by sonication until the turbid cell suspension turned translucent. The lysate obtained is further purified using a nickel containing column (Ni-NTA spin column from QIAGEN) under non-denaturing conditions. Briefly, the lysate is brought up to 300 mM NaCl and 10 mM imidazole and centrifuged at 700×g through the spin column to allow the His-tagged recombinant protein to bind to the nickel column. The column is then washed twice with Wash Buffer (50 mM NaH₂PO_(4,) pH 8.0; 300 mM NaCl; 20 mM imidazole) and is eluted with Elution Buffer (50 mM NaH₂PO₄, pH 8.0; 300 mM NaCl; 250 mM imidazole). All the above procedures are performed at 4° C. The presence of a purified protein of the predicted size is confirmed with SDS-PAGE.

EXAMPLE 6 Evaluation of Activities In Vitro and In Vivo

[0330] The activity of the polypeptides of the invention is assayed by monitoring the effect of such polypeptides on the activity of various signal transduction pathways. One commercially available system for monitoring signal transduction is the Dual-Luciferase™ Reporter Assay System (Promega Corp., Madison, Wis.). Briefly, mammalian cells are co-transfected with (1) a construct expressing the lipoprotein receptor polypeptide to be tested (e.g. CG27, CG153, CG168; or an active fragment; or an active fusion protein), (2) a first reporter construct utilizing a constitutive promoter (as a control for monitoring transfection efficiency), and (3) a second reporter construct that is dependent on a transcription factor or an enhancer element involved in the signal transduction pathway of interest (which serves to monitor the activity of one of several signal transduction pathways).

[0331] Various second reporter constructs are available in both cis- and trans-configurations (from, e.g., Stratagene, La Jolla, Calif.). The trans-configuration involves two constructs, and is used to monitor direct or indirect effects on signal transduction pathways which activate one of several transcription factors. Second reporter constructs for the following transcription factors are currently available from Stratagene: the Elk1 transcription factor for the mitogen-activated protein kinase (MAPK) signaling pathway, the c-Jun transcription factor for the c-Jun N-terminal kinase (JNK) signaling pathway, the CREB transcription factor for the cAMP-dependent kinase (PKA) signaling pathway, the CHOP transcription factor for the p38 kinase signaling pathway, and the c-Fos and ATF2 transcription factors. The cis-configuration is used to monitor direct or indirect effects on six different enhancer elements. Second reporter constructs for the following enhancer elements are currently available from Stratagene: AP-1, CRE, NF-kappaB, SRE, SRF and p53. Other similar set of constructs may be prepared to monitor other transcription factors and enhancer elements known in the art.

[0332] Lipoproteins, or other exogenous ligand, either alone or in combination with other lipoproteins can be added to the transfected cells to determine the effects on candidate signal transduction pathways. Comparison of the effects on different pathways will show specificity of the lipoprotein receptor's biological effects.

[0333] In addition, this system can be used to screen libraries for small molecule drug candidates or lead compounds that disrupt or enhance the effects of the lipoprotein receptor.

EXAMPLE 7 Extension of Sequences and Identification of Variants

[0334] Some of the novel nucleic acids of the present invention were assembled from sequences that were obtained from a cDNA library by methods described in Example 1 above, and in some cases sequences obtained from one or more public databases. The nucleic acids of SEQ ID NO: 16-42 were assembled using an EST sequence as a seed. Then a recursive algorithm was used to extend some of the seed ESTs into an extended assemblage, by pulling additional sequences from different databases (i.e., Hyseq's database containing EST sequences, dbEST version 122, gb pri 122, and UniGene version 122, Genseq 200105 (Derwent), and Genscan, Genemark and Hyseq gene predictions on human genomic sequence from the human genome project) that belong to this assemblage. The algorithm terminated when there was no additional sequences from the above databases that would extend the assemblage. Inclusion of component sequences into the assemblage was based on a BLASTN hit to the extending assemblage with BLAST score greater than 300 and percent identity greater than 95%.

[0335] Using PHRAP (Univ. of Washington) or CAP4 (Paracel), full-length gene cDNA sequences and their corresponding protein sequences were generated from the assemblage. Any frame shifts and incorrect stop codons were corrected by hand editing. During editing, the sequence was checked using FASTXY algorithm against Genbank (i.e., dbEST version 122, gb pri 122, UniGene version 122, Genpept release 122). Other computer programs which may have been used in the editing process were phredPhrap and Consed ((University of Washington) and ed-ready, ed-ext and gc-zip-2 (Hyseq,Inc.)).

EXAMPLE 8 In vitro and In vivo Activity

[0336] A protein of the invention may also be tested for activity in vitro or in vivo using any assays known in the art. For example, assays for HDL, LDL or VLDL uptake or catabolism, beta-amyloid precursor protein (APP) uptake or catabolism, assays for anti-viral effects e.g. on virus assembly or budding, assays for effect on smooth muscle cell cultures, and animal models of atherosclerotic lesions induced by a variety of insults, e.g. high cholesterol diet or endothelial denudation, are described in Perrey et al., Atherosclerosis, 154:51-60 (2001), Kanaki et al., Arteriosclerosis, Thrombosis and Vascular Biol., 19:2687 (1999), Kounnas et al., Cell, 82:331-340 (1995), and Fischer et al., Science, 262:250 (1993), the disclosures of all of which are incorporated by reference in their entirety.

[0337] The present invention is not to be limited in scope by the exemplified embodiments which are intended as illustrations of single aspects of the invention, and compositions and methods which are functionally equivalent are within the scope of the invention. Indeed, numerous modifications and variations in the practice of the invention are expected to occur to those skilled in the art upon consideration of the present preferred embodiments. Consequently, the only limitations which should be placed upon the scope of the invention are those which appear in the appended claims. All references cited within the body of the instant specification are hereby incorporated by reference in their entirety.

0 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 45 <210> SEQ ID NO 1 <211> LENGTH: 1858 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (46)..(1143) <221> NAME/KEY: misc_feature <222> LOCATION: (1758) <223> OTHER INFORMATION: n = a, g, c or t <400> SEQUENCE: 1 cccacgcgtc cgggcctccc tccacctgtc ttctcagagc agata atg gca agc atg 57 Met Ala Ser Met 1 gct gcc gtg ctc acc tgg gct ctg gct ctt ctt tca gcg ttt tcg gcc 105 Ala Ala Val Leu Thr Trp Ala Leu Ala Leu Leu Ser Ala Phe Ser Ala 5 10 15 20 acc cag gca cgg aaa ggc ttc tgg gac tac ttc agc cag acc agc ggg 153 Thr Gln Ala Arg Lys Gly Phe Trp Asp Tyr Phe Ser Gln Thr Ser Gly 25 30 35 gac aaa ggc agg gtg gag cag atc cat cag cag aag atg gct cgc gag 201 Asp Lys Gly Arg Val Glu Gln Ile His Gln Gln Lys Met Ala Arg Glu 40 45 50 ccc gcg acc ctg aaa gac agc ctt gag caa gac ctc aac aat atg aac 249 Pro Ala Thr Leu Lys Asp Ser Leu Glu Gln Asp Leu Asn Asn Met Asn 55 60 65 aag ttc ctg gaa aag ctg agg cct ctg agt ggg agc gag gct cct cgg 297 Lys Phe Leu Glu Lys Leu Arg Pro Leu Ser Gly Ser Glu Ala Pro Arg 70 75 80 ctc cca cag gac ccg gtg ggc atg cgg cgg cag ctg cag gag gag ttg 345 Leu Pro Gln Asp Pro Val Gly Met Arg Arg Gln Leu Gln Glu Glu Leu 85 90 95 100 gag gag gtg aag gct cgc ctc cag ccc tac atg gca gag gcg cac gag 393 Glu Glu Val Lys Ala Arg Leu Gln Pro Tyr Met Ala Glu Ala His Glu 105 110 115 ctg gtg ggc tgg aat ttg gag ggc ttg cgg cag caa ctg aag ccc tac 441 Leu Val Gly Trp Asn Leu Glu Gly Leu Arg Gln Gln Leu Lys Pro Tyr 120 125 130 acg atg gat ctg atg gag cag gtg gcc ctg cgc gtg cag gag ctg cag 489 Thr Met Asp Leu Met Glu Gln Val Ala Leu Arg Val Gln Glu Leu Gln 135 140 145 gag cag ttg cgc gtg gtg ggg gaa gac acc aag gcc cag ttg ctg ggg 537 Glu Gln Leu Arg Val Val Gly Glu Asp Thr Lys Ala Gln Leu Leu Gly 150 155 160 ggc gtg gac gag gct tgg gct ttg ctg cag gga ctg cag agc cgc gtg 585 Gly Val Asp Glu Ala Trp Ala Leu Leu Gln Gly Leu Gln Ser Arg Val 165 170 175 180 gtg cac cac acc ggc cgc ttc aaa gag ctc ttc cac cca tac gcc gag 633 Val His His Thr Gly Arg Phe Lys Glu Leu Phe His Pro Tyr Ala Glu 185 190 195 agc ctg gtg agc ggc atc ggg cgc cac gtg cag gag ctg cac cgc agt 681 Ser Leu Val Ser Gly Ile Gly Arg His Val Gln Glu Leu His Arg Ser 200 205 210 gtg gct ccg cac gcc ccc gcc agc ccc gcg cgc ctc agt cgc tgc gtg 729 Val Ala Pro His Ala Pro Ala Ser Pro Ala Arg Leu Ser Arg Cys Val 215 220 225 cag gtg ctc tcc cgg aag ctc acg ctc aag gcc aag gcc ctg cac gca 777 Gln Val Leu Ser Arg Lys Leu Thr Leu Lys Ala Lys Ala Leu His Ala 230 235 240 cgc atc cag cag aac ctg gac cag ctg cgc gaa gag ctc agc aga gcc 825 Arg Ile Gln Gln Asn Leu Asp Gln Leu Arg Glu Glu Leu Ser Arg Ala 245 250 255 260 ttt gca ggc act ggg act gag gaa ggg gcc ggc ccg gac ccc cag atg 873 Phe Ala Gly Thr Gly Thr Glu Glu Gly Ala Gly Pro Asp Pro Gln Met 265 270 275 ctc tcc gag gag gtg cgc cag cga ctt cag gct ttc cgc cag gac acc 921 Leu Ser Glu Glu Val Arg Gln Arg Leu Gln Ala Phe Arg Gln Asp Thr 280 285 290 tac ctg cag ata gct gcc ttc act cgc gcc atc gac cag gag act gag 969 Tyr Leu Gln Ile Ala Ala Phe Thr Arg Ala Ile Asp Gln Glu Thr Glu 295 300 305 gag gtc cag cag cag ctg gcg cca cct cca cca ggc cac agt gcc ttc 1017 Glu Val Gln Gln Gln Leu Ala Pro Pro Pro Pro Gly His Ser Ala Phe 310 315 320 gcc cca gag ttt caa caa aca gac agt ggc aag gtt ctg agc aag ctg 1065 Ala Pro Glu Phe Gln Gln Thr Asp Ser Gly Lys Val Leu Ser Lys Leu 325 330 335 340 cag gcc cgt ctg gat gac ctg tgg gaa gac atc act cac agc ctt cat 1113 Gln Ala Arg Leu Asp Asp Leu Trp Glu Asp Ile Thr His Ser Leu His 345 350 355 gac cag ggc cac agc cat ctg ggg gac ccc tgaggatcta cctgcccagg 1163 Asp Gln Gly His Ser His Leu Gly Asp Pro 360 365 cccattccca gctccttgtc tggggagcct tggctctgag cctctagcat ggttcagtcc 1223 ttgaaagtgg cctgttgggt ggagggtgga aggtcctgtg caggacaggg aggccaccaa 1283 aggggctgct gtctcctgca tatccagcct cctgcgactc cccaatctgg atgcattaca 1343 ttcaccaggc tttgcaaacc cagcctccca gtgctcattt gggaatgctc atgagttact 1403 ccattcaagg gtgagggagt agggagggag aggcaccatg catgtgggtg attatctgca 1463 agcctgtttg ccgtgatgct ggaagcctgt gccactacat cctggagttt ggctctagtc 1523 acttctggct gcctggtggc cactgctaca gctggtccac agagaggagc acttgtctcc 1583 ccagggctgc catggcagct atcaggggaa tagaagggag aaagagaata tcatggggag 1643 aacatgtgat ggtgtgtgaa tatccctgct ggctctgatg ctggtgggta cgaaaggtgt 1703 gggctgggat aagagagggc agagcccatg ttttctgaca taactctaca cctanataag 1763 ggactgaacc cttccaactg cgggagctcc ttaaaccctt ctggggagca tactgggggc 1823 tcttccccat cttcagcccc ttcctctggg ttccc 1858 <210> SEQ ID NO 2 <211> LENGTH: 366 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 2 Met Ala Ser Met Ala Ala Val Leu Thr Trp Ala Leu Ala Leu Leu Ser 1 5 10 15 Ala Phe Ser Ala Thr Gln Ala Arg Lys Gly Phe Trp Asp Tyr Phe Ser 20 25 30 Gln Thr Ser Gly Asp Lys Gly Arg Val Glu Gln Ile His Gln Gln Lys 35 40 45 Met Ala Arg Glu Pro Ala Thr Leu Lys Asp Ser Leu Glu Gln Asp Leu 50 55 60 Asn Asn Met Asn Lys Phe Leu Glu Lys Leu Arg Pro Leu Ser Gly Ser 65 70 75 80 Glu Ala Pro Arg Leu Pro Gln Asp Pro Val Gly Met Arg Arg Gln Leu 85 90 95 Gln Glu Glu Leu Glu Glu Val Lys Ala Arg Leu Gln Pro Tyr Met Ala 100 105 110 Glu Ala His Glu Leu Val Gly Trp Asn Leu Glu Gly Leu Arg Gln Gln 115 120 125 Leu Lys Pro Tyr Thr Met Asp Leu Met Glu Gln Val Ala Leu Arg Val 130 135 140 Gln Glu Leu Gln Glu Gln Leu Arg Val Val Gly Glu Asp Thr Lys Ala 145 150 155 160 Gln Leu Leu Gly Gly Val Asp Glu Ala Trp Ala Leu Leu Gln Gly Leu 165 170 175 Gln Ser Arg Val Val His His Thr Gly Arg Phe Lys Glu Leu Phe His 180 185 190 Pro Tyr Ala Glu Ser Leu Val Ser Gly Ile Gly Arg His Val Gln Glu 195 200 205 Leu His Arg Ser Val Ala Pro His Ala Pro Ala Ser Pro Ala Arg Leu 210 215 220 Ser Arg Cys Val Gln Val Leu Ser Arg Lys Leu Thr Leu Lys Ala Lys 225 230 235 240 Ala Leu His Ala Arg Ile Gln Gln Asn Leu Asp Gln Leu Arg Glu Glu 245 250 255 Leu Ser Arg Ala Phe Ala Gly Thr Gly Thr Glu Glu Gly Ala Gly Pro 260 265 270 Asp Pro Gln Met Leu Ser Glu Glu Val Arg Gln Arg Leu Gln Ala Phe 275 280 285 Arg Gln Asp Thr Tyr Leu Gln Ile Ala Ala Phe Thr Arg Ala Ile Asp 290 295 300 Gln Glu Thr Glu Glu Val Gln Gln Gln Leu Ala Pro Pro Pro Pro Gly 305 310 315 320 His Ser Ala Phe Ala Pro Glu Phe Gln Gln Thr Asp Ser Gly Lys Val 325 330 335 Leu Ser Lys Leu Gln Ala Arg Leu Asp Asp Leu Trp Glu Asp Ile Thr 340 345 350 His Ser Leu His Asp Gln Gly His Ser His Leu Gly Asp Pro 355 360 365 <210> SEQ ID NO 3 <211> LENGTH: 1425 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (181)..(1146) <400> SEQUENCE: 3 gccaggagcc atgtgggttt ttctaggaac caaaatcact tcccggaatt gaccaactgg 60 tagactcgcc tagaggggaa gcattgtgtc ctagttgagg ctaacagtca gtatccagcc 120 tcaacattca gcagaggccc cagatcagcg tctgagccag gccaacaatg accaaggagg 180 atg gga tcc tgg gtg cag ctc atc aca agc gtc ggg gtg cag caa aac 228 Met Gly Ser Trp Val Gln Leu Ile Thr Ser Val Gly Val Gln Gln Asn 1 5 10 15 cat cca ggc tgg aca gtg gct gga cag ttc caa gaa aag aaa cgc ttc 276 His Pro Gly Trp Thr Val Ala Gly Gln Phe Gln Glu Lys Lys Arg Phe 20 25 30 act gaa gaa gtc att gaa tac ttc cag aag aaa gtt agc cca gtg cat 324 Thr Glu Glu Val Ile Glu Tyr Phe Gln Lys Lys Val Ser Pro Val His 35 40 45 ctg aaa atc ctg ctg act agc gat gaa gcc tgg aag aga ttc gtg cgt 372 Leu Lys Ile Leu Leu Thr Ser Asp Glu Ala Trp Lys Arg Phe Val Arg 50 55 60 gtg gct gaa ttg ccc agg gaa gaa gca gat gct ctc tat gaa gct ctg 420 Val Ala Glu Leu Pro Arg Glu Glu Ala Asp Ala Leu Tyr Glu Ala Leu 65 70 75 80 aag aat ctt aca cca tat gtg gct att gag gac aaa gac atg cag caa 468 Lys Asn Leu Thr Pro Tyr Val Ala Ile Glu Asp Lys Asp Met Gln Gln 85 90 95 aaa gaa cag cag ttt agg gag tgg ttt ttg aaa gag ttt cct caa atc 516 Lys Glu Gln Gln Phe Arg Glu Trp Phe Leu Lys Glu Phe Pro Gln Ile 100 105 110 aga tgg aag att cag gag tcc ata gaa agg ctt cgt gtc att gca aat 564 Arg Trp Lys Ile Gln Glu Ser Ile Glu Arg Leu Arg Val Ile Ala Asn 115 120 125 gag att gaa aag gtc cac aga ggc tgc gtc atc gcc aat gtg gtg tct 612 Glu Ile Glu Lys Val His Arg Gly Cys Val Ile Ala Asn Val Val Ser 130 135 140 ggc tcc act ggc atc ctg tct gtc att ggc gtt atg ttg gca cca ttt 660 Gly Ser Thr Gly Ile Leu Ser Val Ile Gly Val Met Leu Ala Pro Phe 145 150 155 160 aca gca ggg ctg agc ctg agc att act gca gct ggg gta ggg ctg gga 708 Thr Ala Gly Leu Ser Leu Ser Ile Thr Ala Ala Gly Val Gly Leu Gly 165 170 175 ata gca tct gcc acg gct ggg atc gcc tcc agc atc gtg gag aac aca 756 Ile Ala Ser Ala Thr Ala Gly Ile Ala Ser Ser Ile Val Glu Asn Thr 180 185 190 tac aca agg tca gca gaa ctc aca gcc agc agg ctg act gca acc agc 804 Tyr Thr Arg Ser Ala Glu Leu Thr Ala Ser Arg Leu Thr Ala Thr Ser 195 200 205 act gac caa ttg gag gca tta agg gac att ctg cat gac atc aca ccc 852 Thr Asp Gln Leu Glu Ala Leu Arg Asp Ile Leu His Asp Ile Thr Pro 210 215 220 aat gtg ctt tcc ttt gca ctt gat ttt gac gaa gcc aca aaa atg att 900 Asn Val Leu Ser Phe Ala Leu Asp Phe Asp Glu Ala Thr Lys Met Ile 225 230 235 240 gcg aat gat gtc cat aca ctc agg aga tct aaa gcc act gtt gga cgc 948 Ala Asn Asp Val His Thr Leu Arg Arg Ser Lys Ala Thr Val Gly Arg 245 250 255 cct ttg att gct tgg cga tat gta cct ata aat gtt gtt gag aca ctg 996 Pro Leu Ile Ala Trp Arg Tyr Val Pro Ile Asn Val Val Glu Thr Leu 260 265 270 aga aca cgt ggg gcc ccc acc cgg ata gtg aga aaa gta gcc cgg aac 1044 Arg Thr Arg Gly Ala Pro Thr Arg Ile Val Arg Lys Val Ala Arg Asn 275 280 285 ctg ggc aag gcc act tca ggt gtc ctt gtt gtg ctg gat gta gtc aac 1092 Leu Gly Lys Ala Thr Ser Gly Val Leu Val Val Leu Asp Val Val Asn 290 295 300 ctt gtg caa gac tca ctg gac ttg cac aag ggg gca aaa tcc gag tct 1140 Leu Val Gln Asp Ser Leu Asp Leu His Lys Gly Ala Lys Ser Glu Ser 305 310 315 320 gct gag tcgctgaggc agtgggctca ggagctggag gagaatctca atgagctcac 1196 Ala Glu ccatatccat cagagtctaa aagcaggcta ggcccaattg ttgcgggaag tcagggaccc 1256 caaacggagg gactggctga agccatggca gaagaacgtg gattgtgaag atttcatgga 1316 catttattag ttccccaaat taatactttt ataatttcct atgcctgtct ttaccgcaat 1376 ctctaaacac caattgtgaa gatttcatgg acacttatca cttccccaa 1425 <210> SEQ ID NO 4 <211> LENGTH: 322 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 4 Met Gly Ser Trp Val Gln Leu Ile Thr Ser Val Gly Val Gln Gln Asn 1 5 10 15 His Pro Gly Trp Thr Val Ala Gly Gln Phe Gln Glu Lys Lys Arg Phe 20 25 30 Thr Glu Glu Val Ile Glu Tyr Phe Gln Lys Lys Val Ser Pro Val His 35 40 45 Leu Lys Ile Leu Leu Thr Ser Asp Glu Ala Trp Lys Arg Phe Val Arg 50 55 60 Val Ala Glu Leu Pro Arg Glu Glu Ala Asp Ala Leu Tyr Glu Ala Leu 65 70 75 80 Lys Asn Leu Thr Pro Tyr Val Ala Ile Glu Asp Lys Asp Met Gln Gln 85 90 95 Lys Glu Gln Gln Phe Arg Glu Trp Phe Leu Lys Glu Phe Pro Gln Ile 100 105 110 Arg Trp Lys Ile Gln Glu Ser Ile Glu Arg Leu Arg Val Ile Ala Asn 115 120 125 Glu Ile Glu Lys Val His Arg Gly Cys Val Ile Ala Asn Val Val Ser 130 135 140 Gly Ser Thr Gly Ile Leu Ser Val Ile Gly Val Met Leu Ala Pro Phe 145 150 155 160 Thr Ala Gly Leu Ser Leu Ser Ile Thr Ala Ala Gly Val Gly Leu Gly 165 170 175 Ile Ala Ser Ala Thr Ala Gly Ile Ala Ser Ser Ile Val Glu Asn Thr 180 185 190 Tyr Thr Arg Ser Ala Glu Leu Thr Ala Ser Arg Leu Thr Ala Thr Ser 195 200 205 Thr Asp Gln Leu Glu Ala Leu Arg Asp Ile Leu His Asp Ile Thr Pro 210 215 220 Asn Val Leu Ser Phe Ala Leu Asp Phe Asp Glu Ala Thr Lys Met Ile 225 230 235 240 Ala Asn Asp Val His Thr Leu Arg Arg Ser Lys Ala Thr Val Gly Arg 245 250 255 Pro Leu Ile Ala Trp Arg Tyr Val Pro Ile Asn Val Val Glu Thr Leu 260 265 270 Arg Thr Arg Gly Ala Pro Thr Arg Ile Val Arg Lys Val Ala Arg Asn 275 280 285 Leu Gly Lys Ala Thr Ser Gly Val Leu Val Val Leu Asp Val Val Asn 290 295 300 Leu Val Gln Asp Ser Leu Asp Leu His Lys Gly Ala Lys Ser Glu Ser 305 310 315 320 Ala Glu <210> SEQ ID NO 5 <211> LENGTH: 1931 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (18)..(452) <400> SEQUENCE: 5 gaagcttctc gaggacc atg gaa ctt gca ctg ctg tgt ggg ctg gtg gtg 50 Met Glu Leu Ala Leu Leu Cys Gly Leu Val Val 1 5 10 atg gct ggt gtg att cca atc cag ggc ggg atc ctg aac ctg aac aag 98 Met Ala Gly Val Ile Pro Ile Gln Gly Gly Ile Leu Asn Leu Asn Lys 15 20 25 atg gtc aag caa gtg act ggg aaa atg ccc atc ctc tcc tac tgg ccc 146 Met Val Lys Gln Val Thr Gly Lys Met Pro Ile Leu Ser Tyr Trp Pro 30 35 40 tac ggc tgt cac tgc gga cta ggt ggc aga ggc caa ccc aaa gat gcc 194 Tyr Gly Cys His Cys Gly Leu Gly Gly Arg Gly Gln Pro Lys Asp Ala 45 50 55 acg gac tgg tgc tgc cag acc cat gac tgc tgc tat gac cac ctg aag 242 Thr Asp Trp Cys Cys Gln Thr His Asp Cys Cys Tyr Asp His Leu Lys 60 65 70 75 acc cag ggg tgc ggc atc tac aag gac tat tac aga tac aac ttt tcc 290 Thr Gln Gly Cys Gly Ile Tyr Lys Asp Tyr Tyr Arg Tyr Asn Phe Ser 80 85 90 cag ggg aac atc cac tgc tct gac aag gga agc tgg tgt gag cag cag 338 Gln Gly Asn Ile His Cys Ser Asp Lys Gly Ser Trp Cys Glu Gln Gln 95 100 105 ctg tgt gcc tgt gac aag gag gtg gcc ttc tgc ctg aag cgc aac ctg 386 Leu Cys Ala Cys Asp Lys Glu Val Ala Phe Cys Leu Lys Arg Asn Leu 110 115 120 gac acc tac cag aag cga ctg cgt ttc tac tgg cgg ccc cac tgc cgg 434 Asp Thr Tyr Gln Lys Arg Leu Arg Phe Tyr Trp Arg Pro His Cys Arg 125 130 135 ggg cag acc cct ggg tgc tagaagccca caccctctac cctgttcctc 482 Gly Gln Thr Pro Gly Cys 140 145 agcatggagc tctggcatcc ccacctcagt atctaacctg aaccagcctg gcttttcaaa 542 cactccgggg ggaggtagtc ccagcctccc ccggaaccct ctaccaatgc cttctgacct 602 tctgaagctt tccgaatcct cccagttgag gcagtagctg tgtcctctga gggtggatgg 662 gaatcttggg agaagcccaa gcaagggagc cctcagaggt ggtgtttgga ccaaagcatc 722 ggggtggggg aggggtctgc cgctgtcccc cacctgctgg cccccttgtc cttcctcacc 782 ccctccaata tagtctcgga gctacaaccg cagcagccac tataaagggc aatattgatc 842 tttctgtcca tgtggctcta tcttttaaaa cctcaaggcc ctccactgtc ctaagataaa 902 gcctctcata ggcactgggg accctgcaca gtctggccat gtgaccctct ccccaggcaa 962 gctctgaagt ccctgcaggt ggaggccatg cctgtcttaa actcagttgc atccctggtg 1022 cccaaagcaa caccagaacc aagaaggagc tccataaatc cttcttgggt gaagcctaga 1082 caaagccgcc aggtcttgtg gctccaggca ccagagcctt gagtactttc tcctgcctcc 1142 aggcattggc tcagggtgaa ttacaagggg ctactgaatg gctattactt tcatcacgac 1202 tgatccccac ctcctcaggg tcaaagggct actttctgga agtctcccca ggctgactcc 1262 ttctccctga ctgcaagggc tcactccctc ctccaagctc ccacaatgct tcatggctct 1322 gccgcttacc tagcttggcc tagagtggca aatggaactt ctctgatctc ccccaactag 1382 actggagccc ccgaaggatg gagaccatgt ctgtgccatc tctgtttccc ctgttttccc 1442 acatactagg tgctcaattc atgcctgtga atggcgtgag cccataatgg atacacagag 1502 gttgcagcag atggtgtggg tacctcaccc agatatcttc caggcccaag gcccctctcc 1562 ctgagtgagg ccaggtgttg gcagccaact gctccaatct gcctccttcc cctaaatact 1622 gccctggtct agtgggagct gccttccccc tgccccacct ctcccaccaa gaggccacct 1682 gtcactcatg gccaggagag tgacaccatg gagggtacaa ttgccagctc ccccgtgtct 1742 gtgcagcatt gtctgggttg aatgacactc tcaaattgtt cctgggatcg ggctgaggcc 1802 aggcctctcc tggaaccacc tctctgcttg gtctgacccc ttggcctatc cagttttcct 1862 ggttccctca caggtttctc cagaaagtac tccctcagta aagcatttgc acaagaaaaa 1922 aaaaaaaaa 1931 <210> SEQ ID NO 6 <211> LENGTH: 145 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 6 Met Glu Leu Ala Leu Leu Cys Gly Leu Val Val Met Ala Gly Val Ile 1 5 10 15 Pro Ile Gln Gly Gly Ile Leu Asn Leu Asn Lys Met Val Lys Gln Val 20 25 30 Thr Gly Lys Met Pro Ile Leu Ser Tyr Trp Pro Tyr Gly Cys His Cys 35 40 45 Gly Leu Gly Gly Arg Gly Gln Pro Lys Asp Ala Thr Asp Trp Cys Cys 50 55 60 Gln Thr His Asp Cys Cys Tyr Asp His Leu Lys Thr Gln Gly Cys Gly 65 70 75 80 Ile Tyr Lys Asp Tyr Tyr Arg Tyr Asn Phe Ser Gln Gly Asn Ile His 85 90 95 Cys Ser Asp Lys Gly Ser Trp Cys Glu Gln Gln Leu Cys Ala Cys Asp 100 105 110 Lys Glu Val Ala Phe Cys Leu Lys Arg Asn Leu Asp Thr Tyr Gln Lys 115 120 125 Arg Leu Arg Phe Tyr Trp Arg Pro His Cys Arg Gly Gln Thr Pro Gly 130 135 140 Cys 145 <210> SEQ ID NO 7 <211> LENGTH: 1840 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (140)..(1840) <400> SEQUENCE: 7 tcccgggtcg acgatttctt cctgatccca cagcatcgca gagctcggga ggcacagctc 60 acagacacag gaaacacagg actgctattc tgctctcctg cccacggtga tctggtgcca 120 gctggtggaa cagtgggtg atg gcg tcc ctg ctg caa gac cag ctg acc act 172 Met Ala Ser Leu Leu Gln Asp Gln Leu Thr Thr 1 5 10 gat cag gac ttg ctg ctg atg cag gaa ggc atg ccg atg cgc aag gtg 220 Asp Gln Asp Leu Leu Leu Met Gln Glu Gly Met Pro Met Arg Lys Val 15 20 25 agg tcc aaa agc tgg aag aag cta aga tac ttc aga ctt cag aat gac 268 Arg Ser Lys Ser Trp Lys Lys Leu Arg Tyr Phe Arg Leu Gln Asn Asp 30 35 40 ggc atg aca gtc tgg cat gca cgg cag gcc agg ggc agt gcc aag ccc 316 Gly Met Thr Val Trp His Ala Arg Gln Ala Arg Gly Ser Ala Lys Pro 45 50 55 agc ttc tca atc tct gat gtg gag aca ata cgt aat ggc cat gat tcc 364 Ser Phe Ser Ile Ser Asp Val Glu Thr Ile Arg Asn Gly His Asp Ser 60 65 70 75 gag ttg ctg cgt agc ctg gca gag gag ctc ccc ctg gag cag ggc ttc 412 Glu Leu Leu Arg Ser Leu Ala Glu Glu Leu Pro Leu Glu Gln Gly Phe 80 85 90 acc att gtc ttc cat ggc cgc cgc tcc aac ctg gac ctg atg gcc aac 460 Thr Ile Val Phe His Gly Arg Arg Ser Asn Leu Asp Leu Met Ala Asn 95 100 105 agt gtt gag gag gcc cag ata tgg atg cga ggg ctc cag ctg ttg gtg 508 Ser Val Glu Glu Ala Gln Ile Trp Met Arg Gly Leu Gln Leu Leu Val 110 115 120 gat ctt gtc acc agc atg gac cat cag gag cgc ctg gac caa tgg ctg 556 Asp Leu Val Thr Ser Met Asp His Gln Glu Arg Leu Asp Gln Trp Leu 125 130 135 agc gat tgg ttt caa cgt gga gac aaa aat cag gat ggt aag atg agt 604 Ser Asp Trp Phe Gln Arg Gly Asp Lys Asn Gln Asp Gly Lys Met Ser 140 145 150 155 ttc caa gaa gtt cag cgg tta ttg cac cta atg aat gtg gaa atg gac 652 Phe Gln Glu Val Gln Arg Leu Leu His Leu Met Asn Val Glu Met Asp 160 165 170 caa gaa tat gcc ttc agt ctt ttt cag gca gca gac acg tcc cag tct 700 Gln Glu Tyr Ala Phe Ser Leu Phe Gln Ala Ala Asp Thr Ser Gln Ser 175 180 185 gga acc ctg gaa gga gaa gaa ttc gta cag ttc tat aag gca ttg act 748 Gly Thr Leu Glu Gly Glu Glu Phe Val Gln Phe Tyr Lys Ala Leu Thr 190 195 200 aaa cgt gct gag gtg cag gaa ctg ttt gaa agt ttt tca gct gat ggg 796 Lys Arg Ala Glu Val Gln Glu Leu Phe Glu Ser Phe Ser Ala Asp Gly 205 210 215 cag aag ctg act ctg ctg gaa ttt ttg gat ttc ctc caa gag gag cag 844 Gln Lys Leu Thr Leu Leu Glu Phe Leu Asp Phe Leu Gln Glu Glu Gln 220 225 230 235 aag gag aga gac tgc acc tct gag ctt gct ctg gaa ctc att gac cgc 892 Lys Glu Arg Asp Cys Thr Ser Glu Leu Ala Leu Glu Leu Ile Asp Arg 240 245 250 tat gaa cct tca gac agt ggc aaa ctg cgg cat gtg ccg agt atg gat 940 Tyr Glu Pro Ser Asp Ser Gly Lys Leu Arg His Val Pro Ser Met Asp 255 260 265 ggc ttc ctc agc tac ctc tgc tct aag gat gga gac atc ttc aac cca 988 Gly Phe Leu Ser Tyr Leu Cys Ser Lys Asp Gly Asp Ile Phe Asn Pro 270 275 280 gcc tgc ctc ccc atc tat cag gat atg act caa ccc ctg aac cac tac 1036 Ala Cys Leu Pro Ile Tyr Gln Asp Met Thr Gln Pro Leu Asn His Tyr 285 290 295 ttc atc tgc tct tct cat aac acc tac cta gtg ggg gac cag ctt tgc 1084 Phe Ile Cys Ser Ser His Asn Thr Tyr Leu Val Gly Asp Gln Leu Cys 300 305 310 315 ggc cag agc agc gtc gag gga tat ata cgg gcc ctg aag cgg ggg tgc 1132 Gly Gln Ser Ser Val Glu Gly Tyr Ile Arg Ala Leu Lys Arg Gly Cys 320 325 330 cgc tgc gtg gag gtg gat gta tgg gat gga cct agc ggg gaa cct gtc 1180 Arg Cys Val Glu Val Asp Val Trp Asp Gly Pro Ser Gly Glu Pro Val 335 340 345 gtt tac cac gga cac acc ctg acc tcc cgc atc ctg ttc aaa gat gtc 1228 Val Tyr His Gly His Thr Leu Thr Ser Arg Ile Leu Phe Lys Asp Val 350 355 360 gtg gcc aca gta gca cag tat gcc ttc cag aca tca gac tac cca gtc 1276 Val Ala Thr Val Ala Gln Tyr Ala Phe Gln Thr Ser Asp Tyr Pro Val 365 370 375 atc ttg tcc ctg gag acc cac tgc agc tgg gag cag cag cag acc atg 1324 Ile Leu Ser Leu Glu Thr His Cys Ser Trp Glu Gln Gln Gln Thr Met 380 385 390 395 gcc cgt cat ctg act gag atc ctg ggg gag cag ctg ctg agc acc acc 1372 Ala Arg His Leu Thr Glu Ile Leu Gly Glu Gln Leu Leu Ser Thr Thr 400 405 410 ttg gat ggg gtg ctg ccc act cag ctg ccc tcg cct gag gag ctt cgg 1420 Leu Asp Gly Val Leu Pro Thr Gln Leu Pro Ser Pro Glu Glu Leu Arg 415 420 425 agg aag atc ctg gtg aag ggg aag aag tta aca ctt gag gaa gac ctg 1468 Arg Lys Ile Leu Val Lys Gly Lys Lys Leu Thr Leu Glu Glu Asp Leu 430 435 440 gaa tat gag gaa gag gaa gca gaa cct gag ttg gaa gag tca gaa ttg 1516 Glu Tyr Glu Glu Glu Glu Ala Glu Pro Glu Leu Glu Glu Ser Glu Leu 445 450 455 gcg ctg gag tcc cag ttt gag act gag cct gag ccc cag gag cag aac 1564 Ala Leu Glu Ser Gln Phe Glu Thr Glu Pro Glu Pro Gln Glu Gln Asn 460 465 470 475 ctt cag aat aag gac aaa aag aag aaa tcc aag ccc atc ttg tgt cca 1612 Leu Gln Asn Lys Asp Lys Lys Lys Lys Ser Lys Pro Ile Leu Cys Pro 480 485 490 gcc ctc tct tcc ctg gtt atc tac ttg aag tct gtc tca ttc cgc agc 1660 Ala Leu Ser Ser Leu Val Ile Tyr Leu Lys Ser Val Ser Phe Arg Ser 495 500 505 ttc aca cat tca aag gag cac tac cac ttc tac gag ata tca tct ttc 1708 Phe Thr His Ser Lys Glu His Tyr His Phe Tyr Glu Ile Ser Ser Phe 510 515 520 tct gaa acc aag gcc aag cgc ctc atc aag gag gct ggc aat gag ttt 1756 Ser Glu Thr Lys Ala Lys Arg Leu Ile Lys Glu Ala Gly Asn Glu Phe 525 530 535 gtg cag cac aat act cgg cag tta agc cgt gtg tat ccc agc ggc ctg 1804 Val Gln His Asn Thr Arg Gln Leu Ser Arg Val Tyr Pro Ser Gly Leu 540 545 550 555 agg aca ggc tct tcc atc tac aac ccg cag gga tac 1840 Arg Thr Gly Ser Ser Ile Tyr Asn Pro Gln Gly Tyr 560 565 <210> SEQ ID NO 8 <211> LENGTH: 567 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 8 Met Ala Ser Leu Leu Gln Asp Gln Leu Thr Thr Asp Gln Asp Leu Leu 1 5 10 15 Leu Met Gln Glu Gly Met Pro Met Arg Lys Val Arg Ser Lys Ser Trp 20 25 30 Lys Lys Leu Arg Tyr Phe Arg Leu Gln Asn Asp Gly Met Thr Val Trp 35 40 45 His Ala Arg Gln Ala Arg Gly Ser Ala Lys Pro Ser Phe Ser Ile Ser 50 55 60 Asp Val Glu Thr Ile Arg Asn Gly His Asp Ser Glu Leu Leu Arg Ser 65 70 75 80 Leu Ala Glu Glu Leu Pro Leu Glu Gln Gly Phe Thr Ile Val Phe His 85 90 95 Gly Arg Arg Ser Asn Leu Asp Leu Met Ala Asn Ser Val Glu Glu Ala 100 105 110 Gln Ile Trp Met Arg Gly Leu Gln Leu Leu Val Asp Leu Val Thr Ser 115 120 125 Met Asp His Gln Glu Arg Leu Asp Gln Trp Leu Ser Asp Trp Phe Gln 130 135 140 Arg Gly Asp Lys Asn Gln Asp Gly Lys Met Ser Phe Gln Glu Val Gln 145 150 155 160 Arg Leu Leu His Leu Met Asn Val Glu Met Asp Gln Glu Tyr Ala Phe 165 170 175 Ser Leu Phe Gln Ala Ala Asp Thr Ser Gln Ser Gly Thr Leu Glu Gly 180 185 190 Glu Glu Phe Val Gln Phe Tyr Lys Ala Leu Thr Lys Arg Ala Glu Val 195 200 205 Gln Glu Leu Phe Glu Ser Phe Ser Ala Asp Gly Gln Lys Leu Thr Leu 210 215 220 Leu Glu Phe Leu Asp Phe Leu Gln Glu Glu Gln Lys Glu Arg Asp Cys 225 230 235 240 Thr Ser Glu Leu Ala Leu Glu Leu Ile Asp Arg Tyr Glu Pro Ser Asp 245 250 255 Ser Gly Lys Leu Arg His Val Pro Ser Met Asp Gly Phe Leu Ser Tyr 260 265 270 Leu Cys Ser Lys Asp Gly Asp Ile Phe Asn Pro Ala Cys Leu Pro Ile 275 280 285 Tyr Gln Asp Met Thr Gln Pro Leu Asn His Tyr Phe Ile Cys Ser Ser 290 295 300 His Asn Thr Tyr Leu Val Gly Asp Gln Leu Cys Gly Gln Ser Ser Val 305 310 315 320 Glu Gly Tyr Ile Arg Ala Leu Lys Arg Gly Cys Arg Cys Val Glu Val 325 330 335 Asp Val Trp Asp Gly Pro Ser Gly Glu Pro Val Val Tyr His Gly His 340 345 350 Thr Leu Thr Ser Arg Ile Leu Phe Lys Asp Val Val Ala Thr Val Ala 355 360 365 Gln Tyr Ala Phe Gln Thr Ser Asp Tyr Pro Val Ile Leu Ser Leu Glu 370 375 380 Thr His Cys Ser Trp Glu Gln Gln Gln Thr Met Ala Arg His Leu Thr 385 390 395 400 Glu Ile Leu Gly Glu Gln Leu Leu Ser Thr Thr Leu Asp Gly Val Leu 405 410 415 Pro Thr Gln Leu Pro Ser Pro Glu Glu Leu Arg Arg Lys Ile Leu Val 420 425 430 Lys Gly Lys Lys Leu Thr Leu Glu Glu Asp Leu Glu Tyr Glu Glu Glu 435 440 445 Glu Ala Glu Pro Glu Leu Glu Glu Ser Glu Leu Ala Leu Glu Ser Gln 450 455 460 Phe Glu Thr Glu Pro Glu Pro Gln Glu Gln Asn Leu Gln Asn Lys Asp 465 470 475 480 Lys Lys Lys Lys Ser Lys Pro Ile Leu Cys Pro Ala Leu Ser Ser Leu 485 490 495 Val Ile Tyr Leu Lys Ser Val Ser Phe Arg Ser Phe Thr His Ser Lys 500 505 510 Glu His Tyr His Phe Tyr Glu Ile Ser Ser Phe Ser Glu Thr Lys Ala 515 520 525 Lys Arg Leu Ile Lys Glu Ala Gly Asn Glu Phe Val Gln His Asn Thr 530 535 540 Arg Gln Leu Ser Arg Val Tyr Pro Ser Gly Leu Arg Thr Gly Ser Ser 545 550 555 560 Ile Tyr Asn Pro Gln Gly Tyr 565 <210> SEQ ID NO 9 <211> LENGTH: 1384 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 9 ccaactaagc ttgcctaatt tgcttcagaa ttggaagagg gaattgcagc aggaaaatat 60 gtgaagagtt tttaaaccca caaattcttc ttactttaga attagttgtt acattggcag 120 gaaaaaataa atgcagatgt tggaccatgt tggaaacctt gtcaagacag tggattgtct 180 cacacagaat ggaaatgtgg cttctgattc tggtggcgta tatgttccag agaaatgtga 240 attcagtaca tatgccaact aaagctgtgg acccagaagc attcatgaat attagtgaaa 300 tcatccaaca tcaaggctat ccctgtgagg aatatgaagt cgcaactgaa gatgggtata 360 tcctttctgt taacaggatt cctcgaggcc tagtgcaacc taagaagaca ggttccaggc 420 ctgtggtgtt actgcagcat ggcctagttg gaggtgctag caactggatt tccaacctgc 480 ccaacaatag cctgggcttc attctggcag atgctggttt tgacgtgtgg atggggaaca 540 gcaggggaaa cgcctggtct cgaaaacaca agacactctc catagaccaa gatgagttct 600 gggctttcag ttatgatgag atggctaggt ttgaccttcc tgcagtgata aactttattt 660 tgcagaaaac gggccaggaa aagatctatt atgtcggcta ttcacagggc accaccatgg 720 gctttattgc attttccacc atgccagagc tggctcagaa aatcaaaatg tattttgctt 780 tagcacccat agccactgtt aagcatgcaa aaagccccgg gaccaaattt ttgttgctgc 840 cagatatgat gatcaaggga ttgtttggca aaaaagaatt tctgtatcag accagatttc 900 tcagacaact tgttatttac ctttgtggcc aggtgattct tgatcagatt tgtagtaata 960 tcatgttact tctgggtgga ttcaacacca acaatatgaa catgagccga gcaagtgtat 1020 atgctgccca cactcttgct ggaacatctg tgcaaaatat tctacactgg agccaggcag 1080 tgaattctgg tgaactccgg gcatttgact gggggagtga gaccaaaaat ctggaaaaat 1140 gcaatcagcc aactcctgta aggtacagag tcagagatat gacggtccct acagcaatgt 1200 ggacaggagg tcaggactgg ctttcaaatc cagaagacgt gaaaatgctg ctctctgagg 1260 tgaccaacct catctaccat aagaatattc ctgaatgggc tcatgtggat ttcatctggg 1320 gtttggatgc tcctcaccgt atgtacaatg aaatcatcca tctgatgcag caggaggaga 1380 ccat 1384 <210> SEQ ID NO 10 <211> LENGTH: 1915 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (180)..(1046) <400> SEQUENCE: 10 ccgcacgagg gaaagaacat taggaatgcc ttttagtgcc ttgcttcctg aactagctca 60 cagtagcccg gcggcccagg gcaatccgac cacatttcac tctcaccgct gtaggaatcc 120 agatgcaggc caagtacagc agcacgaggg acatgctgga tgatgatggg gacaccacc 179 atg agc ctg cat tct caa gcc tct gcc aca act cgg cat cca gag ccc 227 Met Ser Leu His Ser Gln Ala Ser Ala Thr Thr Arg His Pro Glu Pro 1 5 10 15 cgg cgc aca gag cac agg gct ccc tct tca acg tgg cga cca gtg gcc 275 Arg Arg Thr Glu His Arg Ala Pro Ser Ser Thr Trp Arg Pro Val Ala 20 25 30 ctg acc ctg ctg act ttg tgc ttg gtg ctg ctg ata ggg ctg gca gcc 323 Leu Thr Leu Leu Thr Leu Cys Leu Val Leu Leu Ile Gly Leu Ala Ala 35 40 45 ctg ggg ctt ttg ttt ttt cag tac tac cag ctc tcc aat act ggt caa 371 Leu Gly Leu Leu Phe Phe Gln Tyr Tyr Gln Leu Ser Asn Thr Gly Gln 50 55 60 gac acc att tct caa atg gaa gaa aga tta gga aat acg tcc caa gag 419 Asp Thr Ile Ser Gln Met Glu Glu Arg Leu Gly Asn Thr Ser Gln Glu 65 70 75 80 ttg caa tct ctt caa gtc cag aat ata aag ctt gca gga agt ctg cag 467 Leu Gln Ser Leu Gln Val Gln Asn Ile Lys Leu Ala Gly Ser Leu Gln 85 90 95 cat gtg gct gaa aaa ctc tgt cgt gag ctg tat aac aaa gct gga ggc 515 His Val Ala Glu Lys Leu Cys Arg Glu Leu Tyr Asn Lys Ala Gly Gly 100 105 110 tat aca aga aac atg gtg cca gca tct gct tct tct gag agc ctc agg 563 Tyr Thr Arg Asn Met Val Pro Ala Ser Ala Ser Ser Glu Ser Leu Arg 115 120 125 cag ctt cca cac atg ggg gaa agt gca gca gca cac agg tgc agc cct 611 Gln Leu Pro His Met Gly Glu Ser Ala Ala Ala His Arg Cys Ser Pro 130 135 140 tgt aca gaa caa tgg aaa tgg cat gga gac aat tgc tac cag ttc tat 659 Cys Thr Glu Gln Trp Lys Trp His Gly Asp Asn Cys Tyr Gln Phe Tyr 145 150 155 160 aaa gac agc aaa agt tgg gag gac tgt aaa tat ttc tgc ctt agt gaa 707 Lys Asp Ser Lys Ser Trp Glu Asp Cys Lys Tyr Phe Cys Leu Ser Glu 165 170 175 aac tct acc atg ctg aag ata aac aaa caa gaa gac ctg gaa ttt gcc 755 Asn Ser Thr Met Leu Lys Ile Asn Lys Gln Glu Asp Leu Glu Phe Ala 180 185 190 gcg tct cag agc tac tct gag ttt ttc tac tct tat tgg aca ggg ctt 803 Ala Ser Gln Ser Tyr Ser Glu Phe Phe Tyr Ser Tyr Trp Thr Gly Leu 195 200 205 ttg cgc cct gac agt ggc aag gcc tgg ctg tgg atg gat gga acc cct 851 Leu Arg Pro Asp Ser Gly Lys Ala Trp Leu Trp Met Asp Gly Thr Pro 210 215 220 ttc act tct gaa ctg ttc cat att ata ata gat gtc acc agc cca aga 899 Phe Thr Ser Glu Leu Phe His Ile Ile Ile Asp Val Thr Ser Pro Arg 225 230 235 240 agc aga gac tgt gtg gcc atc ctt aat ggg atg atc ttc tca aag gac 947 Ser Arg Asp Cys Val Ala Ile Leu Asn Gly Met Ile Phe Ser Lys Asp 245 250 255 tgc aaa gaa ttg aag cgt tgt gtc tgt gag aga agg gca gga atg gtg 995 Cys Lys Glu Leu Lys Arg Cys Val Cys Glu Arg Arg Ala Gly Met Val 260 265 270 aag cca gag agc ctc cat gtc ccc cct gaa aca tta ggc gaa ggt gac 1043 Lys Pro Glu Ser Leu His Val Pro Pro Glu Thr Leu Gly Glu Gly Asp 275 280 285 tga ttcgccctct gcaactacaa atagcagagt gagccaggcg gtgccaaagc 1096 aagggctagt tgagacattg ggaaatggaa cataatcagg aaagactatc tctctgacta 1156 gtacaaaatg ggttctcgtg tttcctgttc aggatcacca gcatttctga gcttgggttt 1216 atgcacgtat ttaacagtca caagaagtct tatttacatg ccaccaacca acctcagaaa 1276 cccataatgt catctgcctt cttggcttag agataacttt tagctctctt tcttctcaat 1336 gtctaatatc acctccctgt tttcatgtct tccttacact tggtggaata agaaactttt 1396 tgaagtagag gaaatacatt gaggtaacat ccttttctct gacagtcaag tagtccatca 1456 gaaattggca gtcacttccc agattgtacc agcaaataca caaggaattc tttttgtttg 1516 tttcagttca tactagtccc ttcccaatcc atcagtaaag accccatctg ccttgtccat 1576 gccgtttccc aacagggatg tcacttgata tgagaatctc aaatctcaat gccttataag 1636 cattccttcc tgtgtccatt aagactctga taattgtctc ccctccatag gaatttctcc 1696 caggaaagaa atatatcccc atctccgttt catatcagaa ctaccgtccc cgatattccc 1756 ttcagagaga ttaaagacca gaaaaaaggg gggctttttt tttgcacctg taatagtttc 1816 cggtcctttt ttttttcctt gacccctttt ttttcccttc cgggggtgga gggtttatta 1876 taattaaagg gaataccggg gaaaaaaaaa aaaaagggg 1915 <210> SEQ ID NO 11 <211> LENGTH: 288 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 11 Met Ser Leu His Ser Gln Ala Ser Ala Thr Thr Arg His Pro Glu Pro 1 5 10 15 Arg Arg Thr Glu His Arg Ala Pro Ser Ser Thr Trp Arg Pro Val Ala 20 25 30 Leu Thr Leu Leu Thr Leu Cys Leu Val Leu Leu Ile Gly Leu Ala Ala 35 40 45 Leu Gly Leu Leu Phe Phe Gln Tyr Tyr Gln Leu Ser Asn Thr Gly Gln 50 55 60 Asp Thr Ile Ser Gln Met Glu Glu Arg Leu Gly Asn Thr Ser Gln Glu 65 70 75 80 Leu Gln Ser Leu Gln Val Gln Asn Ile Lys Leu Ala Gly Ser Leu Gln 85 90 95 His Val Ala Glu Lys Leu Cys Arg Glu Leu Tyr Asn Lys Ala Gly Gly 100 105 110 Tyr Thr Arg Asn Met Val Pro Ala Ser Ala Ser Ser Glu Ser Leu Arg 115 120 125 Gln Leu Pro His Met Gly Glu Ser Ala Ala Ala His Arg Cys Ser Pro 130 135 140 Cys Thr Glu Gln Trp Lys Trp His Gly Asp Asn Cys Tyr Gln Phe Tyr 145 150 155 160 Lys Asp Ser Lys Ser Trp Glu Asp Cys Lys Tyr Phe Cys Leu Ser Glu 165 170 175 Asn Ser Thr Met Leu Lys Ile Asn Lys Gln Glu Asp Leu Glu Phe Ala 180 185 190 Ala Ser Gln Ser Tyr Ser Glu Phe Phe Tyr Ser Tyr Trp Thr Gly Leu 195 200 205 Leu Arg Pro Asp Ser Gly Lys Ala Trp Leu Trp Met Asp Gly Thr Pro 210 215 220 Phe Thr Ser Glu Leu Phe His Ile Ile Ile Asp Val Thr Ser Pro Arg 225 230 235 240 Ser Arg Asp Cys Val Ala Ile Leu Asn Gly Met Ile Phe Ser Lys Asp 245 250 255 Cys Lys Glu Leu Lys Arg Cys Val Cys Glu Arg Arg Ala Gly Met Val 260 265 270 Lys Pro Glu Ser Leu His Val Pro Pro Glu Thr Leu Gly Glu Gly Asp 275 280 285 <210> SEQ ID NO 12 <211> LENGTH: 2420 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (200)..(2395) <221> NAME/KEY: misc_feature <222> LOCATION: (2093) <223> OTHER INFORMATION: n = a, g, c or t <221> NAME/KEY: misc_feature <222> LOCATION: (2215) <223> OTHER INFORMATION: d = a or g or t; not c <221> NAME/KEY: misc_feature <222> LOCATION: (2332) <223> OTHER INFORMATION: b = c or g or t; not a <221> NAME/KEY: misc_feature <222> LOCATION: (2396) <223> OTHER INFORMATION: m = a or c <221> NAME/KEY: misc_feature <222> LOCATION: (632) <223> OTHER INFORMATION: Xaa = unknown or other <221> NAME/KEY: misc_feature <222> LOCATION: (672) <223> OTHER INFORMATION: Xaa = unknown or other <221> NAME/KEY: misc_feature <222> LOCATION: (711) <223> OTHER INFORMATION: Xaa = unknown or other <400> SEQUENCE: 12 cgggaggaat ggaaggagaa ggcggaatgt gggagggctc agggggatgt gggagggacg 60 aacggagaag ggggagagag gggggtccag tctcccctgg ccgagcattt tttttttttg 120 gaagtcctag gactaatctc caggaccagc actcttctcc cagcccttag ggtcctgctc 180 ggccaaggcc ttccctgcc atg cga cct gtc agt gtc tgg cag tgg agc ccc 232 Met Arg Pro Val Ser Val Trp Gln Trp Ser Pro 1 5 10 tgg ggg ctg ctg ctg tgc ctg ctg tgc agt tcg tgc ttg ggg tct ccg 280 Trp Gly Leu Leu Leu Cys Leu Leu Cys Ser Ser Cys Leu Gly Ser Pro 15 20 25 tcc cct tcc acg ggc cct gag aag aag gcc ggg agc cag ggg ctt cgg 328 Ser Pro Ser Thr Gly Pro Glu Lys Lys Ala Gly Ser Gln Gly Leu Arg 30 35 40 ttc cgg ctg gct ggc ttc ccc agg aag ccc tac gag ggc cgc gtg gag 376 Phe Arg Leu Ala Gly Phe Pro Arg Lys Pro Tyr Glu Gly Arg Val Glu 45 50 55 ata cag cga gct ggt gaa tgg ggc acc atc tgc gat gat gac ttc acg 424 Ile Gln Arg Ala Gly Glu Trp Gly Thr Ile Cys Asp Asp Asp Phe Thr 60 65 70 75 ctg cag gct gcc cac atc ctc tgc cgg gag ctg ggc ttc aca gag gcc 472 Leu Gln Ala Ala His Ile Leu Cys Arg Glu Leu Gly Phe Thr Glu Ala 80 85 90 aca ggc tgg acc cac agt gcc aaa tat ggc cct gga aca ggc cgc atc 520 Thr Gly Trp Thr His Ser Ala Lys Tyr Gly Pro Gly Thr Gly Arg Ile 95 100 105 tgg ctg gac aac ttg agc tgc agt ggg acc gag cag agt gtg act gaa 568 Trp Leu Asp Asn Leu Ser Cys Ser Gly Thr Glu Gln Ser Val Thr Glu 110 115 120 tgt gcc tcc cgg ggc tgg ggg aac agt gac tgt acg cac gat gag gat 616 Cys Ala Ser Arg Gly Trp Gly Asn Ser Asp Cys Thr His Asp Glu Asp 125 130 135 gct ggg gtc atc tgc aaa gac cag cgc ctc cct ggc ttc tcg gac tcc 664 Ala Gly Val Ile Cys Lys Asp Gln Arg Leu Pro Gly Phe Ser Asp Ser 140 145 150 155 aat gtc att gag gta gag cat cac ctg caa gtg gag gag gtg cga att 712 Asn Val Ile Glu Val Glu His His Leu Gln Val Glu Glu Val Arg Ile 160 165 170 cga ccc gcc gtt ggg tgg ggc aga cga ccc ctg ccc gtg acg gag ggg 760 Arg Pro Ala Val Gly Trp Gly Arg Arg Pro Leu Pro Val Thr Glu Gly 175 180 185 ctg gtg gaa gtc agg ctt cct gac ggc tgg tcg caa gtg tgc gac aaa 808 Leu Val Glu Val Arg Leu Pro Asp Gly Trp Ser Gln Val Cys Asp Lys 190 195 200 ggc tgg agc gcc cac aac agc cac gtg gtc tgc ggg atg ctg ggc ttc 856 Gly Trp Ser Ala His Asn Ser His Val Val Cys Gly Met Leu Gly Phe 205 210 215 ccc agc gaa aag agg gtc aac gcg gcc ttc tac agg ctg cta gcc caa 904 Pro Ser Glu Lys Arg Val Asn Ala Ala Phe Tyr Arg Leu Leu Ala Gln 220 225 230 235 cgg cag caa cac tcc ttt ggt ctg cat ggg gtg gcg tgc gtg ggc acg 952 Arg Gln Gln His Ser Phe Gly Leu His Gly Val Ala Cys Val Gly Thr 240 245 250 gag gcc cac ctc tcc ctc tgt tcc ctg gag ttc tat cgt gcc aat gac 1000 Glu Ala His Leu Ser Leu Cys Ser Leu Glu Phe Tyr Arg Ala Asn Asp 255 260 265 acc gcc agg tgc cct ggg ggg ggc cct gca gtg gtg agc tgt gtg cca 1048 Thr Ala Arg Cys Pro Gly Gly Gly Pro Ala Val Val Ser Cys Val Pro 270 275 280 ggc cct gtc tac gcg gca tcc agt ggc cag aag aag caa caa cag tcg 1096 Gly Pro Val Tyr Ala Ala Ser Ser Gly Gln Lys Lys Gln Gln Gln Ser 285 290 295 aag cct cag ggg gag gtc cgt gtc cgt cta aag ggc ggc gcc cac cct 1144 Lys Pro Gln Gly Glu Val Arg Val Arg Leu Lys Gly Gly Ala His Pro 300 305 310 315 gga gag ggc cgg gta gaa gtc ctg aag gcc agc aca tgg ggc aca gtc 1192 Gly Glu Gly Arg Val Glu Val Leu Lys Ala Ser Thr Trp Gly Thr Val 320 325 330 tgt tac cgc aag tgg gac ctg cat gca gcc agc gtg gtg tgt cgg gag 1240 Cys Tyr Arg Lys Trp Asp Leu His Ala Ala Ser Val Val Cys Arg Glu 335 340 345 ctg ggc ttc ggg agt gct cga gaa gct ctg agt ggc gct cgc atg ggg 1288 Leu Gly Phe Gly Ser Ala Arg Glu Ala Leu Ser Gly Ala Arg Met Gly 350 355 360 cag ggc atg ggt gct atc cac ctg agt gaa gtt cgc tgc tct gga cag 1336 Gln Gly Met Gly Ala Ile His Leu Ser Glu Val Arg Cys Ser Gly Gln 365 370 375 gag ctc tcc ctc tgg aag tgc ccc cac aag aac atc aca gct gag gat 1384 Glu Leu Ser Leu Trp Lys Cys Pro His Lys Asn Ile Thr Ala Glu Asp 380 385 390 395 tgt tca cat agc cag gat gcc ggg gtc cgg tgc aac cta cct tac act 1432 Cys Ser His Ser Gln Asp Ala Gly Val Arg Cys Asn Leu Pro Tyr Thr 400 405 410 ggg gca gag acc agg gtc atc cat tct gtg tca cta cag atc cga ctc 1480 Gly Ala Glu Thr Arg Val Ile His Ser Val Ser Leu Gln Ile Arg Leu 415 420 425 agt ggg ggc cgc agc caa cat gag ggg cga gtc gag gtg caa ata ggg 1528 Ser Gly Gly Arg Ser Gln His Glu Gly Arg Val Glu Val Gln Ile Gly 430 435 440 gga cct ggg ccc ctt cgc tgg ggc ctc atc tgt ggg gat gac tgg ggg 1576 Gly Pro Gly Pro Leu Arg Trp Gly Leu Ile Cys Gly Asp Asp Trp Gly 445 450 455 acc ctg gag gcc atg gtg gcc tgt agg caa ctg ggt ctg ggc tac gcc 1624 Thr Leu Glu Ala Met Val Ala Cys Arg Gln Leu Gly Leu Gly Tyr Ala 460 465 470 475 aac cac ggc ctg cag gag acc tgg tac tgg gac tct ggg aat ata aca 1672 Asn His Gly Leu Gln Glu Thr Trp Tyr Trp Asp Ser Gly Asn Ile Thr 480 485 490 gag gtg gtg atg agt gga gtg cgc tgc aca ggg act gag ctg tcc ctg 1720 Glu Val Val Met Ser Gly Val Arg Cys Thr Gly Thr Glu Leu Ser Leu 495 500 505 gat cag tgt gcc cat cat ggc acc cac atc acc tgc aag agg aca ggg 1768 Asp Gln Cys Ala His His Gly Thr His Ile Thr Cys Lys Arg Thr Gly 510 515 520 acc cgc ttc act gct gga gtc atc tgt tct gag gca tca gat ctg ttg 1816 Thr Arg Phe Thr Ala Gly Val Ile Cys Ser Glu Ala Ser Asp Leu Leu 525 530 535 ctg cac tca gca ctg gtg cag gag acc gcc tac atc gaa gac cgg ccc 1864 Leu His Ser Ala Leu Val Gln Glu Thr Ala Tyr Ile Glu Asp Arg Pro 540 545 550 555 ctg cat atg ttg tac tgt gct gcg gaa gag aac tgc ctg gcc agc tca 1912 Leu His Met Leu Tyr Cys Ala Ala Glu Glu Asn Cys Leu Ala Ser Ser 560 565 570 gcc cgc tca gcc aac tgg ccc tat ggt cac cgg cgt ctg ctc cga ttc 1960 Ala Arg Ser Ala Asn Trp Pro Tyr Gly His Arg Arg Leu Leu Arg Phe 575 580 585 tgc tcc cag atc cac aac ctg gga cga gct gac ttc agg ccc aag gct 2008 Cys Ser Gln Ile His Asn Leu Gly Arg Ala Asp Phe Arg Pro Lys Ala 590 595 600 ggg cgc cac tcc tgg gtg tgg cac gag tgc cat ggg cat tac cac agc 2056 Gly Arg His Ser Trp Val Trp His Glu Cys His Gly His Tyr His Ser 605 610 615 acg gac ttc ttc act cac tat gat atc ctc acc cca nat ggc acc aag 2104 Thr Asp Phe Phe Thr His Tyr Asp Ile Leu Thr Pro Xaa Gly Thr Lys 620 625 630 635 gtg gct gag ggc cac aaa gct agt ttc tgt ctc gaa gac act gag tgt 2152 Val Ala Glu Gly His Lys Ala Ser Phe Cys Leu Glu Asp Thr Glu Cys 640 645 650 cag gag gat gtc tcc aag cgg tat gag tgt gcc aac ttt gga gag caa 2200 Gln Glu Asp Val Ser Lys Arg Tyr Glu Cys Ala Asn Phe Gly Glu Gln 655 660 665 ggc atc act gtg ggd tgc tgg gat ctc tac cgg cat gac att gac tgt 2248 Gly Ile Thr Val Xaa Cys Trp Asp Leu Tyr Arg His Asp Ile Asp Cys 670 675 680 cag tgg att gac atc acg gat gtg aag cca gga aac tac att ctc cag 2296 Gln Trp Ile Asp Ile Thr Asp Val Lys Pro Gly Asn Tyr Ile Leu Gln 685 690 695 gtt gtc atc aac cca aac ttt gaa gta gca gag agb gac ttt acc aac 2344 Val Val Ile Asn Pro Asn Phe Glu Val Ala Glu Xaa Asp Phe Thr Asn 700 705 710 715 aat gca atg aaa tgt aac tgc aaa tat gat gga cat aga atc tgg gtg 2392 Asn Ala Met Lys Cys Asn Cys Lys Tyr Asp Gly His Arg Ile Trp Val 720 725 730 cac macttgccac attggtgatg ccttc 2420 His <210> SEQ ID NO 13 <211> LENGTH: 732 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (632) <223> OTHER INFORMATION: Xaa = unknown or other <221> NAME/KEY: misc_feature <222> LOCATION: (672) <223> OTHER INFORMATION: Xaa = unknown or other <221> NAME/KEY: misc_feature <222> LOCATION: (711) <223> OTHER INFORMATION: Xaa = unknown or other <400> SEQUENCE: 13 Met Arg Pro Val Ser Val Trp Gln Trp Ser Pro Trp Gly Leu Leu Leu 1 5 10 15 Cys Leu Leu Cys Ser Ser Cys Leu Gly Ser Pro Ser Pro Ser Thr Gly 20 25 30 Pro Glu Lys Lys Ala Gly Ser Gln Gly Leu Arg Phe Arg Leu Ala Gly 35 40 45 Phe Pro Arg Lys Pro Tyr Glu Gly Arg Val Glu Ile Gln Arg Ala Gly 50 55 60 Glu Trp Gly Thr Ile Cys Asp Asp Asp Phe Thr Leu Gln Ala Ala His 65 70 75 80 Ile Leu Cys Arg Glu Leu Gly Phe Thr Glu Ala Thr Gly Trp Thr His 85 90 95 Ser Ala Lys Tyr Gly Pro Gly Thr Gly Arg Ile Trp Leu Asp Asn Leu 100 105 110 Ser Cys Ser Gly Thr Glu Gln Ser Val Thr Glu Cys Ala Ser Arg Gly 115 120 125 Trp Gly Asn Ser Asp Cys Thr His Asp Glu Asp Ala Gly Val Ile Cys 130 135 140 Lys Asp Gln Arg Leu Pro Gly Phe Ser Asp Ser Asn Val Ile Glu Val 145 150 155 160 Glu His His Leu Gln Val Glu Glu Val Arg Ile Arg Pro Ala Val Gly 165 170 175 Trp Gly Arg Arg Pro Leu Pro Val Thr Glu Gly Leu Val Glu Val Arg 180 185 190 Leu Pro Asp Gly Trp Ser Gln Val Cys Asp Lys Gly Trp Ser Ala His 195 200 205 Asn Ser His Val Val Cys Gly Met Leu Gly Phe Pro Ser Glu Lys Arg 210 215 220 Val Asn Ala Ala Phe Tyr Arg Leu Leu Ala Gln Arg Gln Gln His Ser 225 230 235 240 Phe Gly Leu His Gly Val Ala Cys Val Gly Thr Glu Ala His Leu Ser 245 250 255 Leu Cys Ser Leu Glu Phe Tyr Arg Ala Asn Asp Thr Ala Arg Cys Pro 260 265 270 Gly Gly Gly Pro Ala Val Val Ser Cys Val Pro Gly Pro Val Tyr Ala 275 280 285 Ala Ser Ser Gly Gln Lys Lys Gln Gln Gln Ser Lys Pro Gln Gly Glu 290 295 300 Val Arg Val Arg Leu Lys Gly Gly Ala His Pro Gly Glu Gly Arg Val 305 310 315 320 Glu Val Leu Lys Ala Ser Thr Trp Gly Thr Val Cys Tyr Arg Lys Trp 325 330 335 Asp Leu His Ala Ala Ser Val Val Cys Arg Glu Leu Gly Phe Gly Ser 340 345 350 Ala Arg Glu Ala Leu Ser Gly Ala Arg Met Gly Gln Gly Met Gly Ala 355 360 365 Ile His Leu Ser Glu Val Arg Cys Ser Gly Gln Glu Leu Ser Leu Trp 370 375 380 Lys Cys Pro His Lys Asn Ile Thr Ala Glu Asp Cys Ser His Ser Gln 385 390 395 400 Asp Ala Gly Val Arg Cys Asn Leu Pro Tyr Thr Gly Ala Glu Thr Arg 405 410 415 Val Ile His Ser Val Ser Leu Gln Ile Arg Leu Ser Gly Gly Arg Ser 420 425 430 Gln His Glu Gly Arg Val Glu Val Gln Ile Gly Gly Pro Gly Pro Leu 435 440 445 Arg Trp Gly Leu Ile Cys Gly Asp Asp Trp Gly Thr Leu Glu Ala Met 450 455 460 Val Ala Cys Arg Gln Leu Gly Leu Gly Tyr Ala Asn His Gly Leu Gln 465 470 475 480 Glu Thr Trp Tyr Trp Asp Ser Gly Asn Ile Thr Glu Val Val Met Ser 485 490 495 Gly Val Arg Cys Thr Gly Thr Glu Leu Ser Leu Asp Gln Cys Ala His 500 505 510 His Gly Thr His Ile Thr Cys Lys Arg Thr Gly Thr Arg Phe Thr Ala 515 520 525 Gly Val Ile Cys Ser Glu Ala Ser Asp Leu Leu Leu His Ser Ala Leu 530 535 540 Val Gln Glu Thr Ala Tyr Ile Glu Asp Arg Pro Leu His Met Leu Tyr 545 550 555 560 Cys Ala Ala Glu Glu Asn Cys Leu Ala Ser Ser Ala Arg Ser Ala Asn 565 570 575 Trp Pro Tyr Gly His Arg Arg Leu Leu Arg Phe Cys Ser Gln Ile His 580 585 590 Asn Leu Gly Arg Ala Asp Phe Arg Pro Lys Ala Gly Arg His Ser Trp 595 600 605 Val Trp His Glu Cys His Gly His Tyr His Ser Thr Asp Phe Phe Thr 610 615 620 His Tyr Asp Ile Leu Thr Pro Xaa Gly Thr Lys Val Ala Glu Gly His 625 630 635 640 Lys Ala Ser Phe Cys Leu Glu Asp Thr Glu Cys Gln Glu Asp Val Ser 645 650 655 Lys Arg Tyr Glu Cys Ala Asn Phe Gly Glu Gln Gly Ile Thr Val Xaa 660 665 670 Cys Trp Asp Leu Tyr Arg His Asp Ile Asp Cys Gln Trp Ile Asp Ile 675 680 685 Thr Asp Val Lys Pro Gly Asn Tyr Ile Leu Gln Val Val Ile Asn Pro 690 695 700 Asn Phe Glu Val Ala Glu Xaa Asp Phe Thr Asn Asn Ala Met Lys Cys 705 710 715 720 Asn Cys Lys Tyr Asp Gly His Arg Ile Trp Val His 725 730 <210> SEQ ID NO 14 <211> LENGTH: 2066 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (149)..(2065) <400> SEQUENCE: 14 cacacgggcg cctcgctcgc gctcacacac gctctgcctc ctctctcccg cacgcgcgca 60 tccctccacc ttccacatcc tgctccaggc aggagaaggc tgactggctg gactcattga 120 gctgaagaat ttccagtgac atttgtaa atg acg ccg ctc gat tcc agg ctc 172 Met Thr Pro Leu Asp Ser Arg Leu 1 5 caa gcg gcc cct gcc gcc gcc gcc gcc gcc ggg ccg aag gtg ccg ccg 220 Gln Ala Ala Pro Ala Ala Ala Ala Ala Ala Gly Pro Lys Val Pro Pro 10 15 20 agc agt ctc cag cgc agg ctt cct tac cgg gcg acc aca atg tcc gag 268 Ser Ser Leu Gln Arg Arg Leu Pro Tyr Arg Ala Thr Thr Met Ser Glu 25 30 35 40 ttt ctc ctc gcc tta ctc act ctc tcg gga tta ttg ccg att gcc agg 316 Phe Leu Leu Ala Leu Leu Thr Leu Ser Gly Leu Leu Pro Ile Ala Arg 45 50 55 gtg ctg acc gtg gga gcc gac cga gat cag cag ttg tgt gat cct ggt 364 Val Leu Thr Val Gly Ala Asp Arg Asp Gln Gln Leu Cys Asp Pro Gly 60 65 70 gaa ttt ctt tgc cac gat cac gtg act tgt gtc tcc cag agc tgg ctg 412 Glu Phe Leu Cys His Asp His Val Thr Cys Val Ser Gln Ser Trp Leu 75 80 85 tgt gat ggg gac cct gac tgc cct gat gat tca gac gag tct tta gat 460 Cys Asp Gly Asp Pro Asp Cys Pro Asp Asp Ser Asp Glu Ser Leu Asp 90 95 100 acc tgt ccc gag gag gta gaa atc aag tgc ccc ttg aat cac att gct 508 Thr Cys Pro Glu Glu Val Glu Ile Lys Cys Pro Leu Asn His Ile Ala 105 110 115 120 tgc ctt ggc acc aac aaa tgt gtt cat tta tcc cag ctg tgc aat ggt 556 Cys Leu Gly Thr Asn Lys Cys Val His Leu Ser Gln Leu Cys Asn Gly 125 130 135 gtc ttg gac tgc cca gat ggg tat gac gaa gga gta cat tgt cag gaa 604 Val Leu Asp Cys Pro Asp Gly Tyr Asp Glu Gly Val His Cys Gln Glu 140 145 150 ctg tta tcc aat tgc caa cag ctg aat tgt cag tat aaa tgt aca atg 652 Leu Leu Ser Asn Cys Gln Gln Leu Asn Cys Gln Tyr Lys Cys Thr Met 155 160 165 gtc aga aat agt aca aga tgt tac tgt gag gat gga ttc gaa ata aca 700 Val Arg Asn Ser Thr Arg Cys Tyr Cys Glu Asp Gly Phe Glu Ile Thr 170 175 180 gaa gat ggg aga agc tgt aaa gat caa gat gaa tgt gct gtt tat ggt 748 Glu Asp Gly Arg Ser Cys Lys Asp Gln Asp Glu Cys Ala Val Tyr Gly 185 190 195 200 aca ggc agc cag acc tgc aga aac aca cat gga tcc tac act tgc agt 796 Thr Gly Ser Gln Thr Cys Arg Asn Thr His Gly Ser Tyr Thr Cys Ser 205 210 215 tgt gtg gaa ggc tac cta atg cag cca gac agc aga tct tgc aag gct 844 Cys Val Glu Gly Tyr Leu Met Gln Pro Asp Ser Arg Ser Cys Lys Ala 220 225 230 aaa att gaa cct aca gat aga cca cgt ata cta tta att gca aat ttt 892 Lys Ile Glu Pro Thr Asp Arg Pro Arg Ile Leu Leu Ile Ala Asn Phe 235 240 245 gaa tca att gag gtt ttc tat ctt aat gga agt aaa att gca act cta 940 Glu Ser Ile Glu Val Phe Tyr Leu Asn Gly Ser Lys Ile Ala Thr Leu 250 255 260 agc tca gtc aat gga aat gaa att cat act ctg gat ttt att tat aat 988 Ser Ser Val Asn Gly Asn Glu Ile His Thr Leu Asp Phe Ile Tyr Asn 265 270 275 280 gaa gat gtg att tgt tgg att gaa tca aga gaa tct tca aat caa ctc 1036 Glu Asp Val Ile Cys Trp Ile Glu Ser Arg Glu Ser Ser Asn Gln Leu 285 290 295 aaa tgt atc cag ata aca aaa gca gga gga tta aca gat gaa tgg aca 1084 Lys Cys Ile Gln Ile Thr Lys Ala Gly Gly Leu Thr Asp Glu Trp Thr 300 305 310 atc aat att ctt caa tcc ttc cac aat gtg caa caa atg gcg att gac 1132 Ile Asn Ile Leu Gln Ser Phe His Asn Val Gln Gln Met Ala Ile Asp 315 320 325 tgg ctc act cga aat ctc tat ttt gtg gac cat gtc ggt gac cgg atc 1180 Trp Leu Thr Arg Asn Leu Tyr Phe Val Asp His Val Gly Asp Arg Ile 330 335 340 ttt gtt tgt aat tcc aac ggt tct gta tgt gtc acc ctg att gat ctg 1228 Phe Val Cys Asn Ser Asn Gly Ser Val Cys Val Thr Leu Ile Asp Leu 345 350 355 360 gag ctt cac aat cct aaa gca ata gca gta gat cca ata gca gga aaa 1276 Glu Leu His Asn Pro Lys Ala Ile Ala Val Asp Pro Ile Ala Gly Lys 365 370 375 ctt ttc ttt act gac tac ggg aat gtc gcc aaa gtg gag aga tgt gac 1324 Leu Phe Phe Thr Asp Tyr Gly Asn Val Ala Lys Val Glu Arg Cys Asp 380 385 390 atg gat ggg atg aac cga aca agg ata att gat tca aag aca gag cag 1372 Met Asp Gly Met Asn Arg Thr Arg Ile Ile Asp Ser Lys Thr Glu Gln 395 400 405 cca gct gca ctg gca cta gac cta gtc aac aaa ttg gtt tac tgg gta 1420 Pro Ala Ala Leu Ala Leu Asp Leu Val Asn Lys Leu Val Tyr Trp Val 410 415 420 gat ctt tac ttg gac tat gtg gga gta gtg gac tat caa gga aaa aat 1468 Asp Leu Tyr Leu Asp Tyr Val Gly Val Val Asp Tyr Gln Gly Lys Asn 425 430 435 440 aga cac act gtc att caa ggc aga caa gtc aga cat ctt tat ggt ata 1516 Arg His Thr Val Ile Gln Gly Arg Gln Val Arg His Leu Tyr Gly Ile 445 450 455 act gtg ttt gaa gat tat ttg tat gca acc aat tct gat aac tac aat 1564 Thr Val Phe Glu Asp Tyr Leu Tyr Ala Thr Asn Ser Asp Asn Tyr Asn 460 465 470 atc gta agg ata aac cga ttt aat ggg act gat att cac tca tta att 1612 Ile Val Arg Ile Asn Arg Phe Asn Gly Thr Asp Ile His Ser Leu Ile 475 480 485 aaa att gag aat gct tgg gga atc cga att tat caa aaa aga act caa 1660 Lys Ile Glu Asn Ala Trp Gly Ile Arg Ile Tyr Gln Lys Arg Thr Gln 490 495 500 cca aca gtc aga agc cat gca tgt gaa gtc gat cca tat gga atg cca 1708 Pro Thr Val Arg Ser His Ala Cys Glu Val Asp Pro Tyr Gly Met Pro 505 510 515 520 ggg ggc tgt tca cac atc tgt cta ctc agc agc agt tac aaa act cgg 1756 Gly Gly Cys Ser His Ile Cys Leu Leu Ser Ser Ser Tyr Lys Thr Arg 525 530 535 act tgt cgc tgc agg act ggc ttc aac ttg gga agt gat ggc agg tca 1804 Thr Cys Arg Cys Arg Thr Gly Phe Asn Leu Gly Ser Asp Gly Arg Ser 540 545 550 tgc aaa aga cca aag aat gag ttg ttc ctc ttt tat ggg aaa gga cgc 1852 Cys Lys Arg Pro Lys Asn Glu Leu Phe Leu Phe Tyr Gly Lys Gly Arg 555 560 565 cca gga att gtt aga gga atg gac ttg aat acc aag ata gct gat gaa 1900 Pro Gly Ile Val Arg Gly Met Asp Leu Asn Thr Lys Ile Ala Asp Glu 570 575 580 tac atg atc ccc ata gaa aat ctg gta aac cct cgt gct tta gac ttt 1948 Tyr Met Ile Pro Ile Glu Asn Leu Val Asn Pro Arg Ala Leu Asp Phe 585 590 595 600 cac gca gaa acc aat tac atc tac ttt gct gac acc acc agt ttc cta 1996 His Ala Glu Thr Asn Tyr Ile Tyr Phe Ala Asp Thr Thr Ser Phe Leu 605 610 615 att ggc cgg cag aag ata gat ggc aca gag aga gaa acc atc ctg aaa 2044 Ile Gly Arg Gln Lys Ile Asp Gly Thr Glu Arg Glu Thr Ile Leu Lys 620 625 630 gat gat ctg gat aat gta gag g 2066 Asp Asp Leu Asp Asn Val Glu 635 <210> SEQ ID NO 15 <211> LENGTH: 639 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 15 Met Thr Pro Leu Asp Ser Arg Leu Gln Ala Ala Pro Ala Ala Ala Ala 1 5 10 15 Ala Ala Gly Pro Lys Val Pro Pro Ser Ser Leu Gln Arg Arg Leu Pro 20 25 30 Tyr Arg Ala Thr Thr Met Ser Glu Phe Leu Leu Ala Leu Leu Thr Leu 35 40 45 Ser Gly Leu Leu Pro Ile Ala Arg Val Leu Thr Val Gly Ala Asp Arg 50 55 60 Asp Gln Gln Leu Cys Asp Pro Gly Glu Phe Leu Cys His Asp His Val 65 70 75 80 Thr Cys Val Ser Gln Ser Trp Leu Cys Asp Gly Asp Pro Asp Cys Pro 85 90 95 Asp Asp Ser Asp Glu Ser Leu Asp Thr Cys Pro Glu Glu Val Glu Ile 100 105 110 Lys Cys Pro Leu Asn His Ile Ala Cys Leu Gly Thr Asn Lys Cys Val 115 120 125 His Leu Ser Gln Leu Cys Asn Gly Val Leu Asp Cys Pro Asp Gly Tyr 130 135 140 Asp Glu Gly Val His Cys Gln Glu Leu Leu Ser Asn Cys Gln Gln Leu 145 150 155 160 Asn Cys Gln Tyr Lys Cys Thr Met Val Arg Asn Ser Thr Arg Cys Tyr 165 170 175 Cys Glu Asp Gly Phe Glu Ile Thr Glu Asp Gly Arg Ser Cys Lys Asp 180 185 190 Gln Asp Glu Cys Ala Val Tyr Gly Thr Gly Ser Gln Thr Cys Arg Asn 195 200 205 Thr His Gly Ser Tyr Thr Cys Ser Cys Val Glu Gly Tyr Leu Met Gln 210 215 220 Pro Asp Ser Arg Ser Cys Lys Ala Lys Ile Glu Pro Thr Asp Arg Pro 225 230 235 240 Arg Ile Leu Leu Ile Ala Asn Phe Glu Ser Ile Glu Val Phe Tyr Leu 245 250 255 Asn Gly Ser Lys Ile Ala Thr Leu Ser Ser Val Asn Gly Asn Glu Ile 260 265 270 His Thr Leu Asp Phe Ile Tyr Asn Glu Asp Val Ile Cys Trp Ile Glu 275 280 285 Ser Arg Glu Ser Ser Asn Gln Leu Lys Cys Ile Gln Ile Thr Lys Ala 290 295 300 Gly Gly Leu Thr Asp Glu Trp Thr Ile Asn Ile Leu Gln Ser Phe His 305 310 315 320 Asn Val Gln Gln Met Ala Ile Asp Trp Leu Thr Arg Asn Leu Tyr Phe 325 330 335 Val Asp His Val Gly Asp Arg Ile Phe Val Cys Asn Ser Asn Gly Ser 340 345 350 Val Cys Val Thr Leu Ile Asp Leu Glu Leu His Asn Pro Lys Ala Ile 355 360 365 Ala Val Asp Pro Ile Ala Gly Lys Leu Phe Phe Thr Asp Tyr Gly Asn 370 375 380 Val Ala Lys Val Glu Arg Cys Asp Met Asp Gly Met Asn Arg Thr Arg 385 390 395 400 Ile Ile Asp Ser Lys Thr Glu Gln Pro Ala Ala Leu Ala Leu Asp Leu 405 410 415 Val Asn Lys Leu Val Tyr Trp Val Asp Leu Tyr Leu Asp Tyr Val Gly 420 425 430 Val Val Asp Tyr Gln Gly Lys Asn Arg His Thr Val Ile Gln Gly Arg 435 440 445 Gln Val Arg His Leu Tyr Gly Ile Thr Val Phe Glu Asp Tyr Leu Tyr 450 455 460 Ala Thr Asn Ser Asp Asn Tyr Asn Ile Val Arg Ile Asn Arg Phe Asn 465 470 475 480 Gly Thr Asp Ile His Ser Leu Ile Lys Ile Glu Asn Ala Trp Gly Ile 485 490 495 Arg Ile Tyr Gln Lys Arg Thr Gln Pro Thr Val Arg Ser His Ala Cys 500 505 510 Glu Val Asp Pro Tyr Gly Met Pro Gly Gly Cys Ser His Ile Cys Leu 515 520 525 Leu Ser Ser Ser Tyr Lys Thr Arg Thr Cys Arg Cys Arg Thr Gly Phe 530 535 540 Asn Leu Gly Ser Asp Gly Arg Ser Cys Lys Arg Pro Lys Asn Glu Leu 545 550 555 560 Phe Leu Phe Tyr Gly Lys Gly Arg Pro Gly Ile Val Arg Gly Met Asp 565 570 575 Leu Asn Thr Lys Ile Ala Asp Glu Tyr Met Ile Pro Ile Glu Asn Leu 580 585 590 Val Asn Pro Arg Ala Leu Asp Phe His Ala Glu Thr Asn Tyr Ile Tyr 595 600 605 Phe Ala Asp Thr Thr Ser Phe Leu Ile Gly Arg Gln Lys Ile Asp Gly 610 615 620 Thr Glu Arg Glu Thr Ile Leu Lys Asp Asp Leu Asp Asn Val Glu 625 630 635 <210> SEQ ID NO 16 <211> LENGTH: 1333 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (280)..(1323) <400> SEQUENCE: 16 gagatccaca cagctcggac cggctggatc ttgctcagtc tctgtcagag gaagatccct 60 tggaggaggc cccgcagcga catggaggga gctgctttgc tgaaagtctt tgtcctctgc 120 atctggaacc aaaatcactt cccggaattg accaactggt agactcgcct agaggggaag 180 cattgtgtcc tagttgaggc taacagtcag tatccagcct caacattcag cagaggcccc 240 agatcagcgt ctgagccagg ccaacaatga ccaaggagg atg gga tcc tgg gtg 294 Met Gly Ser Trp Val 1 5 cag ctc atc aca agc gtc ggg gtg cag caa aac cat cca ggc tgg aca 342 Gln Leu Ile Thr Ser Val Gly Val Gln Gln Asn His Pro Gly Trp Thr 10 15 20 gtg gct gga cag ttc caa gaa aag aaa cgc ttc act gaa gaa gtc att 390 Val Ala Gly Gln Phe Gln Glu Lys Lys Arg Phe Thr Glu Glu Val Ile 25 30 35 gaa tac ttc cag aag aaa gtt agc cca gtg cat ctg aaa atc ctg ctg 438 Glu Tyr Phe Gln Lys Lys Val Ser Pro Val His Leu Lys Ile Leu Leu 40 45 50 act agc gat gaa gcc tgg aag aga ttc gtg cgt gtg gct gaa ttg ccc 486 Thr Ser Asp Glu Ala Trp Lys Arg Phe Val Arg Val Ala Glu Leu Pro 55 60 65 agg gaa gaa gca gat gct ctc tat gaa gct ctg aag aat ctt aca cca 534 Arg Glu Glu Ala Asp Ala Leu Tyr Glu Ala Leu Lys Asn Leu Thr Pro 70 75 80 85 tat gtg gct att gag gac aaa gac atg cag caa aaa gaa cag cag ttt 582 Tyr Val Ala Ile Glu Asp Lys Asp Met Gln Gln Lys Glu Gln Gln Phe 90 95 100 agg gag tgg ttt ttg aaa gag ttt cct caa atc aga tgg aag att cag 630 Arg Glu Trp Phe Leu Lys Glu Phe Pro Gln Ile Arg Trp Lys Ile Gln 105 110 115 gag tcc ata gaa agg ctt cgt gtc att gca aat gag att gaa aag gtc 678 Glu Ser Ile Glu Arg Leu Arg Val Ile Ala Asn Glu Ile Glu Lys Val 120 125 130 cac aga ggc tgc gtc atc gcc aat gtg gtg tct ggc tcc act ggc atc 726 His Arg Gly Cys Val Ile Ala Asn Val Val Ser Gly Ser Thr Gly Ile 135 140 145 ctg tct gtc att ggc gtt atg ttg gca cca ttt aca gca ggg ctg agc 774 Leu Ser Val Ile Gly Val Met Leu Ala Pro Phe Thr Ala Gly Leu Ser 150 155 160 165 ctg agc att act gca gct ggg gta ggg ctg gga ata gca tct gcc acg 822 Leu Ser Ile Thr Ala Ala Gly Val Gly Leu Gly Ile Ala Ser Ala Thr 170 175 180 gct ggg atc gcc tcc agc atc gtg gag aac aca tac aca agg tca gca 870 Ala Gly Ile Ala Ser Ser Ile Val Glu Asn Thr Tyr Thr Arg Ser Ala 185 190 195 gaa ctc aca gcc agc agg ctg act gca acc agc act gac caa ttg gag 918 Glu Leu Thr Ala Ser Arg Leu Thr Ala Thr Ser Thr Asp Gln Leu Glu 200 205 210 gca tta agg gac att ctg cgt gac atc aca ccc aat gtg ctt tct ttt 966 Ala Leu Arg Asp Ile Leu Arg Asp Ile Thr Pro Asn Val Leu Ser Phe 215 220 225 gca ctt gat ttt gac gaa gcc aca aaa atg att gcg aat gat gtc cat 1014 Ala Leu Asp Phe Asp Glu Ala Thr Lys Met Ile Ala Asn Asp Val His 230 235 240 245 aca ctc agg aga tct aaa gcc act gtt gga cgc cct ttg att gct tgg 1062 Thr Leu Arg Arg Ser Lys Ala Thr Val Gly Arg Pro Leu Ile Ala Trp 250 255 260 cga tat gta cct ata aat gtt gtt gag aca ctg aga aca cgt ggg gcc 1110 Arg Tyr Val Pro Ile Asn Val Val Glu Thr Leu Arg Thr Arg Gly Ala 265 270 275 ccc acc cgg ata gtg aga aaa gta gcc cgg aac ctg ggc aag gcc act 1158 Pro Thr Arg Ile Val Arg Lys Val Ala Arg Asn Leu Gly Lys Ala Thr 280 285 290 tca ggt gtc ctt gtt gtg ctg gat gta gtc aac ctt gtg caa gac tca 1206 Ser Gly Val Leu Val Val Leu Asp Val Val Asn Leu Val Gln Asp Ser 295 300 305 ctg gac ttg cac aag ggg gca aaa tcc gag tct gct gag tcg ctg agg 1254 Leu Asp Leu His Lys Gly Ala Lys Ser Glu Ser Ala Glu Ser Leu Arg 310 315 320 325 cag tgg gct cag gag ctg gag gag aat ctc aat gag ctc acc cat atc 1302 Gln Trp Ala Gln Glu Leu Glu Glu Asn Leu Asn Glu Leu Thr His Ile 330 335 340 cat cag agt cta aaa gca ggc taggcccaat 1333 His Gln Ser Leu Lys Ala Gly 345 <210> SEQ ID NO 17 <211> LENGTH: 348 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 17 Met Gly Ser Trp Val Gln Leu Ile Thr Ser Val Gly Val Gln Gln Asn 1 5 10 15 His Pro Gly Trp Thr Val Ala Gly Gln Phe Gln Glu Lys Lys Arg Phe 20 25 30 Thr Glu Glu Val Ile Glu Tyr Phe Gln Lys Lys Val Ser Pro Val His 35 40 45 Leu Lys Ile Leu Leu Thr Ser Asp Glu Ala Trp Lys Arg Phe Val Arg 50 55 60 Val Ala Glu Leu Pro Arg Glu Glu Ala Asp Ala Leu Tyr Glu Ala Leu 65 70 75 80 Lys Asn Leu Thr Pro Tyr Val Ala Ile Glu Asp Lys Asp Met Gln Gln 85 90 95 Lys Glu Gln Gln Phe Arg Glu Trp Phe Leu Lys Glu Phe Pro Gln Ile 100 105 110 Arg Trp Lys Ile Gln Glu Ser Ile Glu Arg Leu Arg Val Ile Ala Asn 115 120 125 Glu Ile Glu Lys Val His Arg Gly Cys Val Ile Ala Asn Val Val Ser 130 135 140 Gly Ser Thr Gly Ile Leu Ser Val Ile Gly Val Met Leu Ala Pro Phe 145 150 155 160 Thr Ala Gly Leu Ser Leu Ser Ile Thr Ala Ala Gly Val Gly Leu Gly 165 170 175 Ile Ala Ser Ala Thr Ala Gly Ile Ala Ser Ser Ile Val Glu Asn Thr 180 185 190 Tyr Thr Arg Ser Ala Glu Leu Thr Ala Ser Arg Leu Thr Ala Thr Ser 195 200 205 Thr Asp Gln Leu Glu Ala Leu Arg Asp Ile Leu Arg Asp Ile Thr Pro 210 215 220 Asn Val Leu Ser Phe Ala Leu Asp Phe Asp Glu Ala Thr Lys Met Ile 225 230 235 240 Ala Asn Asp Val His Thr Leu Arg Arg Ser Lys Ala Thr Val Gly Arg 245 250 255 Pro Leu Ile Ala Trp Arg Tyr Val Pro Ile Asn Val Val Glu Thr Leu 260 265 270 Arg Thr Arg Gly Ala Pro Thr Arg Ile Val Arg Lys Val Ala Arg Asn 275 280 285 Leu Gly Lys Ala Thr Ser Gly Val Leu Val Val Leu Asp Val Val Asn 290 295 300 Leu Val Gln Asp Ser Leu Asp Leu His Lys Gly Ala Lys Ser Glu Ser 305 310 315 320 Ala Glu Ser Leu Arg Gln Trp Ala Gln Glu Leu Glu Glu Asn Leu Asn 325 330 335 Glu Leu Thr His Ile His Gln Ser Leu Lys Ala Gly 340 345 <210> SEQ ID NO 18 <211> LENGTH: 1490 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (151)..(1170) <400> SEQUENCE: 18 agcaaaagag aaaaggagcc aggctgggct tcctgatccc acagcatcgc agagctcggg 60 aggcacagct cacagacaca ggaaacacag gactgctatt ctgctctcct gcccacggtg 120 atctggtgcc agctggtgga acagtgggtg atg gcg tcc ctg ctg caa gac cag 174 Met Ala Ser Leu Leu Gln Asp Gln 1 5 ctg acc act gat cag gac ttg ctg ctg atg cag gaa ggc atg ccg atg 222 Leu Thr Thr Asp Gln Asp Leu Leu Leu Met Gln Glu Gly Met Pro Met 10 15 20 cgc aag gtg agg tcc aaa agc tgg aag aag cta aga tac ttc aga ctt 270 Arg Lys Val Arg Ser Lys Ser Trp Lys Lys Leu Arg Tyr Phe Arg Leu 25 30 35 40 cag aat gac ggc atg aca gtc tgg cat gca cgg cag gcc agg ggc agt 318 Gln Asn Asp Gly Met Thr Val Trp His Ala Arg Gln Ala Arg Gly Ser 45 50 55 gcc aag ccc agc ttc tca atc tct gat gtg gag aca ata cgt aat ggc 366 Ala Lys Pro Ser Phe Ser Ile Ser Asp Val Glu Thr Ile Arg Asn Gly 60 65 70 cat gat tcc gag ttg ctg cgt agc ctg gca gag gag ctc ccc ctg gag 414 His Asp Ser Glu Leu Leu Arg Ser Leu Ala Glu Glu Leu Pro Leu Glu 75 80 85 cag ggc ttc acc att gtc ttc cat ggc cgc cgc tcc aac ctg gac ctg 462 Gln Gly Phe Thr Ile Val Phe His Gly Arg Arg Ser Asn Leu Asp Leu 90 95 100 atg gcc aac agt gtt gag gag gcc cag ata tgg atg cga ggg ctc cag 510 Met Ala Asn Ser Val Glu Glu Ala Gln Ile Trp Met Arg Gly Leu Gln 105 110 115 120 ctg ttg gtg gat ctt gtc acc agc atg gac cat cag gag cgc ctg gac 558 Leu Leu Val Asp Leu Val Thr Ser Met Asp His Gln Glu Arg Leu Asp 125 130 135 caa tgg ctg agc gat tgg ttt caa cgt gga gac aaa aat cag gat ggt 606 Gln Trp Leu Ser Asp Trp Phe Gln Arg Gly Asp Lys Asn Gln Asp Gly 140 145 150 aag atg agt ttc caa gaa gtt cag cgg tta ttg cac cta atg aat gtg 654 Lys Met Ser Phe Gln Glu Val Gln Arg Leu Leu His Leu Met Asn Val 155 160 165 gaa atg gac caa gaa tat gcc ttc agt ctt ttt cag gca gca gac acg 702 Glu Met Asp Gln Glu Tyr Ala Phe Ser Leu Phe Gln Ala Ala Asp Thr 170 175 180 tcc cag tct gga acc ctg gaa gga gaa gaa ttc gta cag ttc tat aag 750 Ser Gln Ser Gly Thr Leu Glu Gly Glu Glu Phe Val Gln Phe Tyr Lys 185 190 195 200 gca ttg act aaa cgt gct gag gtg cag gaa ctg ttt gaa agt ttt tca 798 Ala Leu Thr Lys Arg Ala Glu Val Gln Glu Leu Phe Glu Ser Phe Ser 205 210 215 gct gat ggg cag aag ctg act ctg ctg gaa ttt ttg gat ttc ctc caa 846 Ala Asp Gly Gln Lys Leu Thr Leu Leu Glu Phe Leu Asp Phe Leu Gln 220 225 230 gag gag cag aag gag aga gac tgc acc tct gag ctt gct ctg gaa ctc 894 Glu Glu Gln Lys Glu Arg Asp Cys Thr Ser Glu Leu Ala Leu Glu Leu 235 240 245 att gac cgc tat gaa cct tca gac agt ggc aaa ctg cgg cat gtg ctg 942 Ile Asp Arg Tyr Glu Pro Ser Asp Ser Gly Lys Leu Arg His Val Leu 250 255 260 agt atg gat ggc ttc ctc agc tac ctc tgc tct aag gat gga gac atc 990 Ser Met Asp Gly Phe Leu Ser Tyr Leu Cys Ser Lys Asp Gly Asp Ile 265 270 275 280 ttc aac cca gcc tgc ctc ccc atc tat cag gat atg act caa ccc ctg 1038 Phe Asn Pro Ala Cys Leu Pro Ile Tyr Gln Asp Met Thr Gln Pro Leu 285 290 295 aac cac tac ttc atc tgc tct tct cat aac acc tac cta gtg ggg gac 1086 Asn His Tyr Phe Ile Cys Ser Ser His Asn Thr Tyr Leu Val Gly Asp 300 305 310 cag ctt tgc ggc cag agc agc gtc gag gga tat ata cgg tgc agt ggt 1134 Gln Leu Cys Gly Gln Ser Ser Val Glu Gly Tyr Ile Arg Cys Ser Gly 315 320 325 ggt aga gaa ggg gtc caa ctc atg aga ggg acc atg tagaaaagtg 1180 Gly Arg Glu Gly Val Gln Leu Met Arg Gly Thr Met 330 335 340 aggggagctg tcagtgtcta acagattggg acagtgttgt gggggtttag gggctgagga 1240 gccctggata ccagagacac ttggaggaga tattgaagac tggtgggaga atggtaatga 1300 aaccctatgg gtcaatggaa cttctctttc acaagctatg aaactctcct ggaactcaga 1360 ggccctgaca gatttatatt taacaaatta ataaacagat tgttaaatgg aaggcaatag 1420 agaataggag ttaaaaatat aggttctgga gtcagaccat ctgaaattat attctagctc 1480 ctttacttgg 1490 <210> SEQ ID NO 19 <211> LENGTH: 340 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 19 Met Ala Ser Leu Leu Gln Asp Gln Leu Thr Thr Asp Gln Asp Leu Leu 1 5 10 15 Leu Met Gln Glu Gly Met Pro Met Arg Lys Val Arg Ser Lys Ser Trp 20 25 30 Lys Lys Leu Arg Tyr Phe Arg Leu Gln Asn Asp Gly Met Thr Val Trp 35 40 45 His Ala Arg Gln Ala Arg Gly Ser Ala Lys Pro Ser Phe Ser Ile Ser 50 55 60 Asp Val Glu Thr Ile Arg Asn Gly His Asp Ser Glu Leu Leu Arg Ser 65 70 75 80 Leu Ala Glu Glu Leu Pro Leu Glu Gln Gly Phe Thr Ile Val Phe His 85 90 95 Gly Arg Arg Ser Asn Leu Asp Leu Met Ala Asn Ser Val Glu Glu Ala 100 105 110 Gln Ile Trp Met Arg Gly Leu Gln Leu Leu Val Asp Leu Val Thr Ser 115 120 125 Met Asp His Gln Glu Arg Leu Asp Gln Trp Leu Ser Asp Trp Phe Gln 130 135 140 Arg Gly Asp Lys Asn Gln Asp Gly Lys Met Ser Phe Gln Glu Val Gln 145 150 155 160 Arg Leu Leu His Leu Met Asn Val Glu Met Asp Gln Glu Tyr Ala Phe 165 170 175 Ser Leu Phe Gln Ala Ala Asp Thr Ser Gln Ser Gly Thr Leu Glu Gly 180 185 190 Glu Glu Phe Val Gln Phe Tyr Lys Ala Leu Thr Lys Arg Ala Glu Val 195 200 205 Gln Glu Leu Phe Glu Ser Phe Ser Ala Asp Gly Gln Lys Leu Thr Leu 210 215 220 Leu Glu Phe Leu Asp Phe Leu Gln Glu Glu Gln Lys Glu Arg Asp Cys 225 230 235 240 Thr Ser Glu Leu Ala Leu Glu Leu Ile Asp Arg Tyr Glu Pro Ser Asp 245 250 255 Ser Gly Lys Leu Arg His Val Leu Ser Met Asp Gly Phe Leu Ser Tyr 260 265 270 Leu Cys Ser Lys Asp Gly Asp Ile Phe Asn Pro Ala Cys Leu Pro Ile 275 280 285 Tyr Gln Asp Met Thr Gln Pro Leu Asn His Tyr Phe Ile Cys Ser Ser 290 295 300 His Asn Thr Tyr Leu Val Gly Asp Gln Leu Cys Gly Gln Ser Ser Val 305 310 315 320 Glu Gly Tyr Ile Arg Cys Ser Gly Gly Arg Glu Gly Val Gln Leu Met 325 330 335 Arg Gly Thr Met 340 <210> SEQ ID NO 20 <211> LENGTH: 2035 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (189)..(1415) <400> SEQUENCE: 20 ccaactaagc ttgcctaatt tgcttcagaa ttggaagagg gaattgcagc aggaaaatat 60 gtgaagagtt tttaaaccca caaattcttc ttactttaga attagttgtt acattggcag 120 gaaaaaataa atgcagatgt tggaccatgt tggaaacctt gtcaagacag tggattgtct 180 cacacaga atg gaa atg tgg ctt ctg att ctg gtg gcg tat atg ttc cag 230 Met Glu Met Trp Leu Leu Ile Leu Val Ala Tyr Met Phe Gln 1 5 10 aga aat gtg aat tca gta cat atg cca act aaa gct gtg gac cca gaa 278 Arg Asn Val Asn Ser Val His Met Pro Thr Lys Ala Val Asp Pro Glu 15 20 25 30 gca ttc atg aat att agt gaa atc atc caa cat caa ggc tat ccc tgt 326 Ala Phe Met Asn Ile Ser Glu Ile Ile Gln His Gln Gly Tyr Pro Cys 35 40 45 gag gaa tat gaa gtc gca act gaa gat ggg tat atc ctt tct gtt aac 374 Glu Glu Tyr Glu Val Ala Thr Glu Asp Gly Tyr Ile Leu Ser Val Asn 50 55 60 agg att cct cga ggc cta gtg caa cct aag aag aca ggt tcc agg cct 422 Arg Ile Pro Arg Gly Leu Val Gln Pro Lys Lys Thr Gly Ser Arg Pro 65 70 75 gtg gtg tta ctg cag cat ggc cta gtt gga ggt gct agc aac tgg att 470 Val Val Leu Leu Gln His Gly Leu Val Gly Gly Ala Ser Asn Trp Ile 80 85 90 tcc aac ctg ccc aac aat agc ctg ggc ttc att ctg gca gat gct ggt 518 Ser Asn Leu Pro Asn Asn Ser Leu Gly Phe Ile Leu Ala Asp Ala Gly 95 100 105 110 ttt gac gtg tgg atg ggg aac agc agg gga aac gcc tgg tct cga aaa 566 Phe Asp Val Trp Met Gly Asn Ser Arg Gly Asn Ala Trp Ser Arg Lys 115 120 125 cac aag aca ctc tcc ata gac caa gat gag ttc tgg gct ttc agt tat 614 His Lys Thr Leu Ser Ile Asp Gln Asp Glu Phe Trp Ala Phe Ser Tyr 130 135 140 gat gag atg gct agg ttt gac ctt cct gca gtg ata aac ttt att ttg 662 Asp Glu Met Ala Arg Phe Asp Leu Pro Ala Val Ile Asn Phe Ile Leu 145 150 155 cag aaa acg ggc cag gaa aag atc tat tat gtc ggc tat tca cag ggc 710 Gln Lys Thr Gly Gln Glu Lys Ile Tyr Tyr Val Gly Tyr Ser Gln Gly 160 165 170 acc acc atg ggc ttt att gca ttt tcc acc atg cca gag ctg gct cag 758 Thr Thr Met Gly Phe Ile Ala Phe Ser Thr Met Pro Glu Leu Ala Gln 175 180 185 190 aaa atc aaa atg tat ttt gct tta gca ccc ata gcc act gtt aag cat 806 Lys Ile Lys Met Tyr Phe Ala Leu Ala Pro Ile Ala Thr Val Lys His 195 200 205 gca aaa agc ccc ggg acc aaa ttt ttg ttg ctg cca gat atg atg atc 854 Ala Lys Ser Pro Gly Thr Lys Phe Leu Leu Leu Pro Asp Met Met Ile 210 215 220 aag gga ttg ttt ggc aaa aaa gaa ttt ctg tat cag acc aga ttt ctc 902 Lys Gly Leu Phe Gly Lys Lys Glu Phe Leu Tyr Gln Thr Arg Phe Leu 225 230 235 aga caa ctt gtt att tac ctt tgt ggc cag gtg att ctt gat cag att 950 Arg Gln Leu Val Ile Tyr Leu Cys Gly Gln Val Ile Leu Asp Gln Ile 240 245 250 tgt agt aat atc atg tta ctt ctg ggt gga ttc aac acc aac aat atg 998 Cys Ser Asn Ile Met Leu Leu Leu Gly Gly Phe Asn Thr Asn Asn Met 255 260 265 270 aac atg agc cga gca agt gta tat gct gcc cac act ctt gct gga aca 1046 Asn Met Ser Arg Ala Ser Val Tyr Ala Ala His Thr Leu Ala Gly Thr 275 280 285 tct gtg caa aat att cta cac tgg agc cag gca gtg aat tct ggt gaa 1094 Ser Val Gln Asn Ile Leu His Trp Ser Gln Ala Val Asn Ser Gly Glu 290 295 300 ctc cgg gca ttt gac tgg ggg agt gag acc aaa aat ctg gaa aaa tgc 1142 Leu Arg Ala Phe Asp Trp Gly Ser Glu Thr Lys Asn Leu Glu Lys Cys 305 310 315 aat cag cca act cct gta agg tac aga gtc aga gat atg acg gtc cct 1190 Asn Gln Pro Thr Pro Val Arg Tyr Arg Val Arg Asp Met Thr Val Pro 320 325 330 aca gca atg tgg aca gga ggt cag gac tgg ctt tca aat cca gaa gac 1238 Thr Ala Met Trp Thr Gly Gly Gln Asp Trp Leu Ser Asn Pro Glu Asp 335 340 345 350 gtg aaa atg ctg ctc tct gag gtg acc aac ctc atc tac cat aag aat 1286 Val Lys Met Leu Leu Ser Glu Val Thr Asn Leu Ile Tyr His Lys Asn 355 360 365 att cct gaa tgg gct cat gtg gat ttc atc tgg ggt ttg gat gct cct 1334 Ile Pro Glu Trp Ala His Val Asp Phe Ile Trp Gly Leu Asp Ala Pro 370 375 380 cac cgt atg tac aat gaa atc atc cat ctg atg cag cag gag gag acc 1382 His Arg Met Tyr Asn Glu Ile Ile His Leu Met Gln Gln Glu Glu Thr 385 390 395 aac ctt tcc cag gga cgg tgt gag gcc gta ttg tgaagcatct gacactgacg 1435 Asn Leu Ser Gln Gly Arg Cys Glu Ala Val Leu 400 405 atcttaggac aacctcctga gggatggggc taggacccat gaaggcagaa ttatggagag 1495 cagagaccta gtatacattt ttcagattcc ctgcacttgg cactaaatcc gacacttaca 1555 tttacatttt ttttctgtaa attaaagtac ttattaggta aatagaggtt ttgtatgcta 1615 ttatatattc taccatcttg aagggtaggt tttacctgat agccagaaaa tatctagaca 1675 ttctctatat cattcaggta aatctcttta aaacacctat tgttttttct ataagccata 1735 tttttggagc actaaagtaa aatggcaaat tgggacagat attgaggtct ggagtctgtg 1795 gattattgtt gactttgaca aaataagcta gacattttca ccttgttgcc acagagacat 1855 aacactacct caggaagctg agctgcttta aggacaacaa caacaaaatc agtgttacag 1915 tatggatgaa atctatgtta agcattctca gaataaggcc aagttttata gttgcatctc 1975 agggaagaaa attttatagg atgtttatga gttctccaat aaatgcattc tgcattacat 2035 <210> SEQ ID NO 21 <211> LENGTH: 409 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 21 Met Glu Met Trp Leu Leu Ile Leu Val Ala Tyr Met Phe Gln Arg Asn 1 5 10 15 Val Asn Ser Val His Met Pro Thr Lys Ala Val Asp Pro Glu Ala Phe 20 25 30 Met Asn Ile Ser Glu Ile Ile Gln His Gln Gly Tyr Pro Cys Glu Glu 35 40 45 Tyr Glu Val Ala Thr Glu Asp Gly Tyr Ile Leu Ser Val Asn Arg Ile 50 55 60 Pro Arg Gly Leu Val Gln Pro Lys Lys Thr Gly Ser Arg Pro Val Val 65 70 75 80 Leu Leu Gln His Gly Leu Val Gly Gly Ala Ser Asn Trp Ile Ser Asn 85 90 95 Leu Pro Asn Asn Ser Leu Gly Phe Ile Leu Ala Asp Ala Gly Phe Asp 100 105 110 Val Trp Met Gly Asn Ser Arg Gly Asn Ala Trp Ser Arg Lys His Lys 115 120 125 Thr Leu Ser Ile Asp Gln Asp Glu Phe Trp Ala Phe Ser Tyr Asp Glu 130 135 140 Met Ala Arg Phe Asp Leu Pro Ala Val Ile Asn Phe Ile Leu Gln Lys 145 150 155 160 Thr Gly Gln Glu Lys Ile Tyr Tyr Val Gly Tyr Ser Gln Gly Thr Thr 165 170 175 Met Gly Phe Ile Ala Phe Ser Thr Met Pro Glu Leu Ala Gln Lys Ile 180 185 190 Lys Met Tyr Phe Ala Leu Ala Pro Ile Ala Thr Val Lys His Ala Lys 195 200 205 Ser Pro Gly Thr Lys Phe Leu Leu Leu Pro Asp Met Met Ile Lys Gly 210 215 220 Leu Phe Gly Lys Lys Glu Phe Leu Tyr Gln Thr Arg Phe Leu Arg Gln 225 230 235 240 Leu Val Ile Tyr Leu Cys Gly Gln Val Ile Leu Asp Gln Ile Cys Ser 245 250 255 Asn Ile Met Leu Leu Leu Gly Gly Phe Asn Thr Asn Asn Met Asn Met 260 265 270 Ser Arg Ala Ser Val Tyr Ala Ala His Thr Leu Ala Gly Thr Ser Val 275 280 285 Gln Asn Ile Leu His Trp Ser Gln Ala Val Asn Ser Gly Glu Leu Arg 290 295 300 Ala Phe Asp Trp Gly Ser Glu Thr Lys Asn Leu Glu Lys Cys Asn Gln 305 310 315 320 Pro Thr Pro Val Arg Tyr Arg Val Arg Asp Met Thr Val Pro Thr Ala 325 330 335 Met Trp Thr Gly Gly Gln Asp Trp Leu Ser Asn Pro Glu Asp Val Lys 340 345 350 Met Leu Leu Ser Glu Val Thr Asn Leu Ile Tyr His Lys Asn Ile Pro 355 360 365 Glu Trp Ala His Val Asp Phe Ile Trp Gly Leu Asp Ala Pro His Arg 370 375 380 Met Tyr Asn Glu Ile Ile His Leu Met Gln Gln Glu Glu Thr Asn Leu 385 390 395 400 Ser Gln Gly Arg Cys Glu Ala Val Leu 405 <210> SEQ ID NO 22 <211> LENGTH: 2224 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (82)..(921) <221> NAME/KEY: misc_feature <222> LOCATION: (2205) <223> OTHER INFORMATION: N = A or C or G or T <400> SEQUENCE: 22 tgcttcctga actagctcac agtagcccgg cggcccaggg caatccgacc acatttcact 60 ctcaccgctg taggaatcca g atg cag gcc aag tac agc agc acg agg gac 111 Met Gln Ala Lys Tyr Ser Ser Thr Arg Asp 1 5 10 atg ctg gat gat gat ggg gac acc acc atg agc ctg cat tct caa gcc 159 Met Leu Asp Asp Asp Gly Asp Thr Thr Met Ser Leu His Ser Gln Ala 15 20 25 tct gcc aca act cgg cat cca gag ccc cgg cgc aca gag cac agg gct 207 Ser Ala Thr Thr Arg His Pro Glu Pro Arg Arg Thr Glu His Arg Ala 30 35 40 ccc tct tca acg tgg cga cca gtg gcc ctg acc ctg ctg act ttg tgc 255 Pro Ser Ser Thr Trp Arg Pro Val Ala Leu Thr Leu Leu Thr Leu Cys 45 50 55 ttg gtg ctg ctg ata ggg ctg gca gcc ctg ggg ctt ttg ttt ttt cag 303 Leu Val Leu Leu Ile Gly Leu Ala Ala Leu Gly Leu Leu Phe Phe Gln 60 65 70 tac tac cag ctc tcc aat act ggt caa gac acc att tct caa atg gaa 351 Tyr Tyr Gln Leu Ser Asn Thr Gly Gln Asp Thr Ile Ser Gln Met Glu 75 80 85 90 gaa aga tta gga aat acg tcc caa gag ttg caa tct ctt caa gtc cag 399 Glu Arg Leu Gly Asn Thr Ser Gln Glu Leu Gln Ser Leu Gln Val Gln 95 100 105 aat ata aag ctt gca gga agt ctg cag cat gtg gct gaa aaa ctc tgt 447 Asn Ile Lys Leu Ala Gly Ser Leu Gln His Val Ala Glu Lys Leu Cys 110 115 120 cgt gag ctg tat aac aaa gct gga gca cac agg tgc agc cct tgt aca 495 Arg Glu Leu Tyr Asn Lys Ala Gly Ala His Arg Cys Ser Pro Cys Thr 125 130 135 gaa caa tgg aaa tgg cat gga gac aat tgc tac cag ttc tat aaa gac 543 Glu Gln Trp Lys Trp His Gly Asp Asn Cys Tyr Gln Phe Tyr Lys Asp 140 145 150 agc aaa agt tgg gag gac tgt aaa tat ttc tgc ctt agt gaa aac tct 591 Ser Lys Ser Trp Glu Asp Cys Lys Tyr Phe Cys Leu Ser Glu Asn Ser 155 160 165 170 acc atg ctg aag ata aac aaa caa gaa gac ctg gaa ttt gcc gcg tct 639 Thr Met Leu Lys Ile Asn Lys Gln Glu Asp Leu Glu Phe Ala Ala Ser 175 180 185 cag agc tac tct gag ttt ttc tac tct tat tgg aca ggg ctt ttg cgc 687 Gln Ser Tyr Ser Glu Phe Phe Tyr Ser Tyr Trp Thr Gly Leu Leu Arg 190 195 200 cct gac agt ggc aag gcc tgg ctg tgg atg gat gga acc cct ttc act 735 Pro Asp Ser Gly Lys Ala Trp Leu Trp Met Asp Gly Thr Pro Phe Thr 205 210 215 tct gaa ctg ttc cat att ata ata gat gtc acc agc cca aga agc aga 783 Ser Glu Leu Phe His Ile Ile Ile Asp Val Thr Ser Pro Arg Ser Arg 220 225 230 gac tgt gtg gcc atc ctt aat ggg atg atc ttc tca aag gac tgc aaa 831 Asp Cys Val Ala Ile Leu Asn Gly Met Ile Phe Ser Lys Asp Cys Lys 235 240 245 250 gaa ttg aag cgt tgt gtc tgt gag aga agg gca gga atg gtg aag cca 879 Glu Leu Lys Arg Cys Val Cys Glu Arg Arg Ala Gly Met Val Lys Pro 255 260 265 gag agc ctc cat gtc ccc cct gaa aca tta ggc gaa ggt gac 921 Glu Ser Leu His Val Pro Pro Glu Thr Leu Gly Glu Gly Asp 270 275 280 tgattcgccc tctgcaacta caaatagcag agtgagccag gcggtgccaa agcaagggct 981 agttgagaca ttgggaaatg gaacataatc aggaaagact atctctctga ctagtacaaa 1041 atgggttctc gtgtttcctg ttcaggatca ccagcatttc tgagcttggg tttatgcacg 1101 tatttaacag tcacaagaag tcttatttac atgccaccaa ccaacctcag aaacccataa 1161 tgtcatctgc cttcttggct tagagataac ttttagctct ctttcttctc aatgtctaat 1221 atcacctccc tgttttcatg tcttccttac acttggtgga ataagaaact ttttgaagta 1281 gaggaaatac attgaggtaa catccttttc tctgacagtc aagtagtcca tcagaaattg 1341 gcagtcactt cccagattgt accagcaaat acacaaggaa ttctttttgt ttgtttcagt 1401 tcatactagt cccttcccaa tccatcagta aagaccccat ctgccttgtc catgccgttt 1461 cccaacaggg atgtcacttg atatgagaat ctcaaatctc aatgccttat aagcattcct 1521 tcctgtgtcc attaagactc tgataattgt ctcccctcca taggaatttc tcccaggaaa 1581 gaaatatatc cccatctccg tttcatatca gaactaccgt ccccgatatt cccttcagag 1641 agattaaaga ccagaaaaaa gtgagcctct tcatctgcac ctgtaatagt ttcagttcct 1701 attttcttcc attgacccat atttatacct ttcaggtact gaagatttaa taataataaa 1761 tgtaaatact gtgaagtgtg tgtgatttta caatggactt atggttggtg ggaaaattca 1821 gcatggaaat gcttttcaaa atatgatagc ggtcattatt ttgattgtgc cttactgaaa 1881 gtttttgggg aatttacaag agtactgatt acatgattat ctggagaaaa taagatgtct 1941 ttgaaataca tgttggcttc aagaaaacag ttttaacgtt ttcctaaaat gaaatctttt 2001 gaggtgagct tatggcatca acacatggtt gatgaggaag ctgagttgca ttagtgcaca 2061 tgatttccag tcaggtcatg ggaaatgaac agagacagtg acatctttgt agctgctcct 2121 ttgtgaggca cttctttctt gagatgactc catgcacaaa tataacaggg atcattggga 2181 atgacaccat cacagccacc aagnttattg ggttactgat aat 2224 <210> SEQ ID NO 23 <211> LENGTH: 280 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 23 Met Gln Ala Lys Tyr Ser Ser Thr Arg Asp Met Leu Asp Asp Asp Gly 1 5 10 15 Asp Thr Thr Met Ser Leu His Ser Gln Ala Ser Ala Thr Thr Arg His 20 25 30 Pro Glu Pro Arg Arg Thr Glu His Arg Ala Pro Ser Ser Thr Trp Arg 35 40 45 Pro Val Ala Leu Thr Leu Leu Thr Leu Cys Leu Val Leu Leu Ile Gly 50 55 60 Leu Ala Ala Leu Gly Leu Leu Phe Phe Gln Tyr Tyr Gln Leu Ser Asn 65 70 75 80 Thr Gly Gln Asp Thr Ile Ser Gln Met Glu Glu Arg Leu Gly Asn Thr 85 90 95 Ser Gln Glu Leu Gln Ser Leu Gln Val Gln Asn Ile Lys Leu Ala Gly 100 105 110 Ser Leu Gln His Val Ala Glu Lys Leu Cys Arg Glu Leu Tyr Asn Lys 115 120 125 Ala Gly Ala His Arg Cys Ser Pro Cys Thr Glu Gln Trp Lys Trp His 130 135 140 Gly Asp Asn Cys Tyr Gln Phe Tyr Lys Asp Ser Lys Ser Trp Glu Asp 145 150 155 160 Cys Lys Tyr Phe Cys Leu Ser Glu Asn Ser Thr Met Leu Lys Ile Asn 165 170 175 Lys Gln Glu Asp Leu Glu Phe Ala Ala Ser Gln Ser Tyr Ser Glu Phe 180 185 190 Phe Tyr Ser Tyr Trp Thr Gly Leu Leu Arg Pro Asp Ser Gly Lys Ala 195 200 205 Trp Leu Trp Met Asp Gly Thr Pro Phe Thr Ser Glu Leu Phe His Ile 210 215 220 Ile Ile Asp Val Thr Ser Pro Arg Ser Arg Asp Cys Val Ala Ile Leu 225 230 235 240 Asn Gly Met Ile Phe Ser Lys Asp Cys Lys Glu Leu Lys Arg Cys Val 245 250 255 Cys Glu Arg Arg Ala Gly Met Val Lys Pro Glu Ser Leu His Val Pro 260 265 270 Pro Glu Thr Leu Gly Glu Gly Asp 275 280 <210> SEQ ID NO 24 <211> LENGTH: 996 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (38)..(979) <400> SEQUENCE: 24 ccgaccacat ttcactctca ccgctgtggg aatccag atg cag gcc aag tac agc 55 Met Gln Ala Lys Tyr Ser 1 5 agc acg atg gac atg ctg gat gat gat ggg gac acc acc atg agc ctg 103 Ser Thr Met Asp Met Leu Asp Asp Asp Gly Asp Thr Thr Met Ser Leu 10 15 20 cat tct caa gcc tct gcc aca act cgg cat cca gag ccc cgg cgc aca 151 His Ser Gln Ala Ser Ala Thr Thr Arg His Pro Glu Pro Arg Arg Thr 25 30 35 gag cac agg gct ccc tct tca acg tgg cga cca gtg gcc ctg acc ctg 199 Glu His Arg Ala Pro Ser Ser Thr Trp Arg Pro Val Ala Leu Thr Leu 40 45 50 ctg act ttg tgc ttg gtg ctg ctg ata ggg ctg gca gcc ctg ggg ctt 247 Leu Thr Leu Cys Leu Val Leu Leu Ile Gly Leu Ala Ala Leu Gly Leu 55 60 65 70 ttg ttt ttt cag tac tac cag ctc tcc aat act ggt caa gac acc att 295 Leu Phe Phe Gln Tyr Tyr Gln Leu Ser Asn Thr Gly Gln Asp Thr Ile 75 80 85 tct caa atg gaa gaa aga tta gga aat acg tcc caa gag ttg caa tct 343 Ser Gln Met Glu Glu Arg Leu Gly Asn Thr Ser Gln Glu Leu Gln Ser 90 95 100 ctt caa gtc cag aat ata aag ctt gca gga agt ctg cag cat gtg gct 391 Leu Gln Val Gln Asn Ile Lys Leu Ala Gly Ser Leu Gln His Val Ala 105 110 115 gaa aaa ctc tgt cgt gag ctg tat aac aaa gct gga ggc tat aca aga 439 Glu Lys Leu Cys Arg Glu Leu Tyr Asn Lys Ala Gly Gly Tyr Thr Arg 120 125 130 aac atg gtg cca gca tct gct tct tct gag agc ctc agg cag ctt cca 487 Asn Met Val Pro Ala Ser Ala Ser Ser Glu Ser Leu Arg Gln Leu Pro 135 140 145 150 cac atg ggg gaa agt gca gca gca cac agg tgc agc cct tgt aca gaa 535 His Met Gly Glu Ser Ala Ala Ala His Arg Cys Ser Pro Cys Thr Glu 155 160 165 caa tgg aaa tgg cat gga gac aat tgc tac cag ttc tat aaa gac agc 583 Gln Trp Lys Trp His Gly Asp Asn Cys Tyr Gln Phe Tyr Lys Asp Ser 170 175 180 aaa agt tgg gag gac tgt aaa tat ttc tgc ctt agt gaa aac tct acc 631 Lys Ser Trp Glu Asp Cys Lys Tyr Phe Cys Leu Ser Glu Asn Ser Thr 185 190 195 atg ctg aag ata aac aaa caa gaa gac ctg gaa ttt gcc gcg tct cag 679 Met Leu Lys Ile Asn Lys Gln Glu Asp Leu Glu Phe Ala Ala Ser Gln 200 205 210 agc tac tct gag ttt ttc tac tct tat tgg aca ggg ctt ttg cgc cct 727 Ser Tyr Ser Glu Phe Phe Tyr Ser Tyr Trp Thr Gly Leu Leu Arg Pro 215 220 225 230 gac agt ggc aag gcc tgg ctg tgg atg gat gga acc cct ttc act tct 775 Asp Ser Gly Lys Ala Trp Leu Trp Met Asp Gly Thr Pro Phe Thr Ser 235 240 245 gaa ctg ttc cat att ata ata gat gtc acc agc cca aga agc aga gac 823 Glu Leu Phe His Ile Ile Ile Asp Val Thr Ser Pro Arg Ser Arg Asp 250 255 260 tgt gtg gcc atc ctt aat ggg atg atc ttc tca aag gac tgc aaa gaa 871 Cys Val Ala Ile Leu Asn Gly Met Ile Phe Ser Lys Asp Cys Lys Glu 265 270 275 ttg aag cgt tgt gtc tgt gag aga agg gca gga atg gtg aag cca gag 919 Leu Lys Arg Cys Val Cys Glu Arg Arg Ala Gly Met Val Lys Pro Glu 280 285 290 agc ctc cat gtc ccc cct gaa aca tta ggc gaa ggt gac atg cat cat 967 Ser Leu His Val Pro Pro Glu Thr Leu Gly Glu Gly Asp Met His His 295 300 305 310 cat cat cat cat tagcctaggt tctagac 996 His His His His <210> SEQ ID NO 25 <211> LENGTH: 314 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 25 Met Gln Ala Lys Tyr Ser Ser Thr Met Asp Met Leu Asp Asp Asp Gly 1 5 10 15 Asp Thr Thr Met Ser Leu His Ser Gln Ala Ser Ala Thr Thr Arg His 20 25 30 Pro Glu Pro Arg Arg Thr Glu His Arg Ala Pro Ser Ser Thr Trp Arg 35 40 45 Pro Val Ala Leu Thr Leu Leu Thr Leu Cys Leu Val Leu Leu Ile Gly 50 55 60 Leu Ala Ala Leu Gly Leu Leu Phe Phe Gln Tyr Tyr Gln Leu Ser Asn 65 70 75 80 Thr Gly Gln Asp Thr Ile Ser Gln Met Glu Glu Arg Leu Gly Asn Thr 85 90 95 Ser Gln Glu Leu Gln Ser Leu Gln Val Gln Asn Ile Lys Leu Ala Gly 100 105 110 Ser Leu Gln His Val Ala Glu Lys Leu Cys Arg Glu Leu Tyr Asn Lys 115 120 125 Ala Gly Gly Tyr Thr Arg Asn Met Val Pro Ala Ser Ala Ser Ser Glu 130 135 140 Ser Leu Arg Gln Leu Pro His Met Gly Glu Ser Ala Ala Ala His Arg 145 150 155 160 Cys Ser Pro Cys Thr Glu Gln Trp Lys Trp His Gly Asp Asn Cys Tyr 165 170 175 Gln Phe Tyr Lys Asp Ser Lys Ser Trp Glu Asp Cys Lys Tyr Phe Cys 180 185 190 Leu Ser Glu Asn Ser Thr Met Leu Lys Ile Asn Lys Gln Glu Asp Leu 195 200 205 Glu Phe Ala Ala Ser Gln Ser Tyr Ser Glu Phe Phe Tyr Ser Tyr Trp 210 215 220 Thr Gly Leu Leu Arg Pro Asp Ser Gly Lys Ala Trp Leu Trp Met Asp 225 230 235 240 Gly Thr Pro Phe Thr Ser Glu Leu Phe His Ile Ile Ile Asp Val Thr 245 250 255 Ser Pro Arg Ser Arg Asp Cys Val Ala Ile Leu Asn Gly Met Ile Phe 260 265 270 Ser Lys Asp Cys Lys Glu Leu Lys Arg Cys Val Cys Glu Arg Arg Ala 275 280 285 Gly Met Val Lys Pro Glu Ser Leu His Val Pro Pro Glu Thr Leu Gly 290 295 300 Glu Gly Asp Met His His His His His His 305 310 <210> SEQ ID NO 26 <211> LENGTH: 2125 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (82)..(822) <221> NAME/KEY: misc_feature <222> LOCATION: (2106) <223> OTHER INFORMATION: n = A or C or G or T <400> SEQUENCE: 26 tgcttcctga actagctcac agtagcccgg cggcccaggg caatccgacc acatttcact 60 ctcaccgctg taggaatcca g atg cag gcc aag tac agc agc acg agg gac 111 Met Gln Ala Lys Tyr Ser Ser Thr Arg Asp 1 5 10 atg ctg gat gat gat ggg gac acc acc atg agc ctg cat tct caa gcc 159 Met Leu Asp Asp Asp Gly Asp Thr Thr Met Ser Leu His Ser Gln Ala 15 20 25 tct gcc aca act cgg cat cca gag ccc cgg cgc aca gtt ttt cag tac 207 Ser Ala Thr Thr Arg His Pro Glu Pro Arg Arg Thr Val Phe Gln Tyr 30 35 40 tac cag ctc tcc aat act ggt caa gac acc att tct caa atg gaa gaa 255 Tyr Gln Leu Ser Asn Thr Gly Gln Asp Thr Ile Ser Gln Met Glu Glu 45 50 55 aga tta gga aat acg tcc caa gag ttg caa tct ctt caa gtc cag aat 303 Arg Leu Gly Asn Thr Ser Gln Glu Leu Gln Ser Leu Gln Val Gln Asn 60 65 70 ata aag ctt gca gga agt ctg cag cat gtg gct gaa aaa ctc tgt cgt 351 Ile Lys Leu Ala Gly Ser Leu Gln His Val Ala Glu Lys Leu Cys Arg 75 80 85 90 gag ctg tat aac aaa gct gga gca cac agg tgc agc cct tgt aca gaa 399 Glu Leu Tyr Asn Lys Ala Gly Ala His Arg Cys Ser Pro Cys Thr Glu 95 100 105 caa tgg aaa tgg cat gga gac aat tgc tac cag ttc tat aaa gac agc 447 Gln Trp Lys Trp His Gly Asp Asn Cys Tyr Gln Phe Tyr Lys Asp Ser 110 115 120 aaa agt tgg gag gac tgt aaa tat ttc tgc ctt agt gaa aac tct acc 495 Lys Ser Trp Glu Asp Cys Lys Tyr Phe Cys Leu Ser Glu Asn Ser Thr 125 130 135 atg ctg aag ata aac aaa caa gaa gac ctg gaa ttt gcc gcg tct cag 543 Met Leu Lys Ile Asn Lys Gln Glu Asp Leu Glu Phe Ala Ala Ser Gln 140 145 150 agc tac tct gag ttt ttc tac tct tat tgg aca ggg ctt ttg cgc cct 591 Ser Tyr Ser Glu Phe Phe Tyr Ser Tyr Trp Thr Gly Leu Leu Arg Pro 155 160 165 170 gac agt ggc aag gcc tgg ctg tgg atg gat gga acc cct ttc act tct 639 Asp Ser Gly Lys Ala Trp Leu Trp Met Asp Gly Thr Pro Phe Thr Ser 175 180 185 gaa ctg ttc cat att ata ata gat gtc acc agc cca aga agc aga gac 687 Glu Leu Phe His Ile Ile Ile Asp Val Thr Ser Pro Arg Ser Arg Asp 190 195 200 tgt gtg gcc atc ctt aat ggg atg atc ttc tca aag gac tgc aaa gaa 735 Cys Val Ala Ile Leu Asn Gly Met Ile Phe Ser Lys Asp Cys Lys Glu 205 210 215 ttg aag cgt tgt gtc tgt gag aga agg gca gga atg gtg aag cca gag 783 Leu Lys Arg Cys Val Cys Glu Arg Arg Ala Gly Met Val Lys Pro Glu 220 225 230 agc ctc cat gtc ccc cct gaa aca tta ggc gaa ggt gac tgattcgccc 832 Ser Leu His Val Pro Pro Glu Thr Leu Gly Glu Gly Asp 235 240 245 tctgcaacta caaatagcag agtgagccag gcggtgccaa agcaagggct agttgagaca 892 ttgggaaatg gaacataatc aggaaagact atctctctga ctagtacaaa atgggttctc 952 gtgtttcctg ttcaggatca ccagcatttc tgagcttggg tttatgcacg tatttaacag 1012 tcacaagaag tcttatttac atgccaccaa ccaacctcag aaacccataa tgtcatctgc 1072 cttcttggct tagagataac ttttagctct ctttcttctc aatgtctaat atcacctccc 1132 tgttttcatg tcttccttac acttggtgga ataagaaact ttttgaagta gaggaaatac 1192 attgaggtaa catccttttc tctgacagtc aagtagtcca tcagaaattg gcagtcactt 1252 cccagattgt accagcaaat acacaaggaa ttctttttgt ttgtttcagt tcatactagt 1312 cccttcccaa tccatcagta aagaccccat ctgccttgtc catgccgttt cccaacaggg 1372 atgtcacttg atatgagaat ctcaaatctc aatgccttat aagcattcct tcctgtgtcc 1432 attaagactc tgataattgt ctcccctcca taggaatttc tcccaggaaa gaaatatatc 1492 cccatctccg tttcatatca gaactaccgt ccccgatatt cccttcagag agattaaaga 1552 ccagaaaaaa gtgagcctct tcatctgcac ctgtaatagt ttcagttcct attttcttcc 1612 attgacccat atttatacct ttcaggtact gaagatttaa taataataaa tgtaaatact 1672 gtgaagtgtg tgtgatttta caatggactt atggttggtg ggaaaattca gcatggaaat 1732 gcttttcaaa atatgatagc ggtcattatt ttgattgtgc cttactgaaa gtttttgggg 1792 aatttacaag agtactgatt acatgattat ctggagaaaa taagatgtct ttgaaataca 1852 tgttggcttc aagaaaacag ttttaacgtt ttcctaaaat gaaatctttt gaggtgagct 1912 tatggcatca acacatggtt gatgaggaag ctgagttgca ttagtgcaca tgatttccag 1972 tcaggtcatg ggaaatgaac agagacagtg acatctttgt agctgctcct ttgtgaggca 2032 cttctttctt gagatgactc catgcacaaa tataacaggg atcattggga atgacaccat 2092 cacagccacc aagnttattg ggttactgat aat 2125 <210> SEQ ID NO 27 <211> LENGTH: 247 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 27 Met Gln Ala Lys Tyr Ser Ser Thr Arg Asp Met Leu Asp Asp Asp Gly 1 5 10 15 Asp Thr Thr Met Ser Leu His Ser Gln Ala Ser Ala Thr Thr Arg His 20 25 30 Pro Glu Pro Arg Arg Thr Val Phe Gln Tyr Tyr Gln Leu Ser Asn Thr 35 40 45 Gly Gln Asp Thr Ile Ser Gln Met Glu Glu Arg Leu Gly Asn Thr Ser 50 55 60 Gln Glu Leu Gln Ser Leu Gln Val Gln Asn Ile Lys Leu Ala Gly Ser 65 70 75 80 Leu Gln His Val Ala Glu Lys Leu Cys Arg Glu Leu Tyr Asn Lys Ala 85 90 95 Gly Ala His Arg Cys Ser Pro Cys Thr Glu Gln Trp Lys Trp His Gly 100 105 110 Asp Asn Cys Tyr Gln Phe Tyr Lys Asp Ser Lys Ser Trp Glu Asp Cys 115 120 125 Lys Tyr Phe Cys Leu Ser Glu Asn Ser Thr Met Leu Lys Ile Asn Lys 130 135 140 Gln Glu Asp Leu Glu Phe Ala Ala Ser Gln Ser Tyr Ser Glu Phe Phe 145 150 155 160 Tyr Ser Tyr Trp Thr Gly Leu Leu Arg Pro Asp Ser Gly Lys Ala Trp 165 170 175 Leu Trp Met Asp Gly Thr Pro Phe Thr Ser Glu Leu Phe His Ile Ile 180 185 190 Ile Asp Val Thr Ser Pro Arg Ser Arg Asp Cys Val Ala Ile Leu Asn 195 200 205 Gly Met Ile Phe Ser Lys Asp Cys Lys Glu Leu Lys Arg Cys Val Cys 210 215 220 Glu Arg Arg Ala Gly Met Val Lys Pro Glu Ser Leu His Val Pro Pro 225 230 235 240 Glu Thr Leu Gly Glu Gly Asp 245 <210> SEQ ID NO 28 <211> LENGTH: 5059 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (199)..(2457) <400> SEQUENCE: 28 cgggaggaat ggaaggagaa ggcggaatgt gggagggctc agggggatgt gggagggacg 60 aacggagaag ggggagagag gggggtccag tctcccctgg ccgagcattt ttttttttgg 120 aagtcctagg actgatctcc aggaccagca ctcttctccc agcccttagg gtcctgctcg 180 gccaaggcct tccctgcc atg cga cct gtc agt gtc tgg cag tgg agc ccc 231 Met Arg Pro Val Ser Val Trp Gln Trp Ser Pro 1 5 10 tgg ggg ctg ctg ctg tgc ctg ctg tgc agt tcg tgc ttg ggg tct ccg 279 Trp Gly Leu Leu Leu Cys Leu Leu Cys Ser Ser Cys Leu Gly Ser Pro 15 20 25 tcc cct tcc acg ggc cct gag aag aag gcc ggg agc cag ggg ctt cgg 327 Ser Pro Ser Thr Gly Pro Glu Lys Lys Ala Gly Ser Gln Gly Leu Arg 30 35 40 ttc cgg ctg gct ggc ttc ccc agg aag ccc tac gag ggc cgc gtg gag 375 Phe Arg Leu Ala Gly Phe Pro Arg Lys Pro Tyr Glu Gly Arg Val Glu 45 50 55 ata cag cga gct ggt gaa tgg ggc acc atc tgc gat gat gac ttc acg 423 Ile Gln Arg Ala Gly Glu Trp Gly Thr Ile Cys Asp Asp Asp Phe Thr 60 65 70 75 ctg cag gct gcc cac atc ctc tgc cgg gag ctg ggc ttc aca gag gcc 471 Leu Gln Ala Ala His Ile Leu Cys Arg Glu Leu Gly Phe Thr Glu Ala 80 85 90 aca ggc tgg acc cac agt gcc aaa tat ggc cct gga aca ggc cgc atc 519 Thr Gly Trp Thr His Ser Ala Lys Tyr Gly Pro Gly Thr Gly Arg Ile 95 100 105 tgg ctg gac aac ttg agc tgc agt ggg acc gag cag agt gtg act gaa 567 Trp Leu Asp Asn Leu Ser Cys Ser Gly Thr Glu Gln Ser Val Thr Glu 110 115 120 tgt gcc tcc cgg ggc tgg ggg aac agt gac tgt acg cac gat gag gat 615 Cys Ala Ser Arg Gly Trp Gly Asn Ser Asp Cys Thr His Asp Glu Asp 125 130 135 gct ggg gtc atc tgc aaa gac cag cgc ctc cct ggc ttc tcg gac tcc 663 Ala Gly Val Ile Cys Lys Asp Gln Arg Leu Pro Gly Phe Ser Asp Ser 140 145 150 155 aat gtc att gag gta gag cat cac ctg caa gtg gag gag gtg cga att 711 Asn Val Ile Glu Val Glu His His Leu Gln Val Glu Glu Val Arg Ile 160 165 170 cga ccc gcc gtt ggg tgg ggc aga cga ccc ctg ccc gtg acg gag ggg 759 Arg Pro Ala Val Gly Trp Gly Arg Arg Pro Leu Pro Val Thr Glu Gly 175 180 185 ctg gtg gaa gtc agg ctt cct gac ggc tgg tcg caa gtg tgc gac aaa 807 Leu Val Glu Val Arg Leu Pro Asp Gly Trp Ser Gln Val Cys Asp Lys 190 195 200 ggc tgg agc gcc cac aac agc cac gtg gtc tgc ggg atg ctg ggc ttc 855 Gly Trp Ser Ala His Asn Ser His Val Val Cys Gly Met Leu Gly Phe 205 210 215 ccc agc gaa aag agg gtc aac gcg gcc ttc tac agg ctg cta gcc caa 903 Pro Ser Glu Lys Arg Val Asn Ala Ala Phe Tyr Arg Leu Leu Ala Gln 220 225 230 235 cgg cag caa cac tcc ttt ggt ctg cat ggg gtg gcg tgc gtg ggc acg 951 Arg Gln Gln His Ser Phe Gly Leu His Gly Val Ala Cys Val Gly Thr 240 245 250 gag gcc cac ctc tcc ctc tgt tcc ctg gag ttc tat cgt gcc aat gac 999 Glu Ala His Leu Ser Leu Cys Ser Leu Glu Phe Tyr Arg Ala Asn Asp 255 260 265 acc gcc agg tgc cct ggg ggg ggc cct gca gtg gtg agc tgt gtg cca 1047 Thr Ala Arg Cys Pro Gly Gly Gly Pro Ala Val Val Ser Cys Val Pro 270 275 280 ggc cct gtc tac gcg gca tcc agt ggc cag aag aag caa caa cag tcg 1095 Gly Pro Val Tyr Ala Ala Ser Ser Gly Gln Lys Lys Gln Gln Gln Ser 285 290 295 aag cct cag ggg gag gtc cgt gtc cgt cta aag ggc ggc gcc cac cct 1143 Lys Pro Gln Gly Glu Val Arg Val Arg Leu Lys Gly Gly Ala His Pro 300 305 310 315 gga gag ggc cgg gta gaa gtc ctg aag gcc agc aca tgg ggc aca gtc 1191 Gly Glu Gly Arg Val Glu Val Leu Lys Ala Ser Thr Trp Gly Thr Val 320 325 330 tgt tac cgc aag tgg gac ctg cat gca gcc agc gtg gtg tgt cgg gag 1239 Cys Tyr Arg Lys Trp Asp Leu His Ala Ala Ser Val Val Cys Arg Glu 335 340 345 ctg ggc ttc ggg agt gct cga gaa gct ctg agt ggc gct cgc atg ggg 1287 Leu Gly Phe Gly Ser Ala Arg Glu Ala Leu Ser Gly Ala Arg Met Gly 350 355 360 cag ggc atg ggt gct atc cac ctg agt gaa gtt cgc tgc tct gga cag 1335 Gln Gly Met Gly Ala Ile His Leu Ser Glu Val Arg Cys Ser Gly Gln 365 370 375 gag ctc tcc ctc tgg aag tgc ccc cac aag aac atc aca gct gag gat 1383 Glu Leu Ser Leu Trp Lys Cys Pro His Lys Asn Ile Thr Ala Glu Asp 380 385 390 395 tgt tca cat agc cag gat gcc ggg gtc cgg tgc aac cta cct tac act 1431 Cys Ser His Ser Gln Asp Ala Gly Val Arg Cys Asn Leu Pro Tyr Thr 400 405 410 ggg gca gag acc agg atc cga ctc agt ggg ggc cgc agc caa cat gag 1479 Gly Ala Glu Thr Arg Ile Arg Leu Ser Gly Gly Arg Ser Gln His Glu 415 420 425 ggg cga gtc gag gtg caa ata ggg gga cct ggg ccc ctt cgc tgg ggc 1527 Gly Arg Val Glu Val Gln Ile Gly Gly Pro Gly Pro Leu Arg Trp Gly 430 435 440 ctc atc tgt ggg gat gac tgg ggg acc ctg gag gcc atg gtg gcc tgt 1575 Leu Ile Cys Gly Asp Asp Trp Gly Thr Leu Glu Ala Met Val Ala Cys 445 450 455 agg caa ctg ggt ctg ggc tac gcc aac cac ggc ctg cag gag acc tgg 1623 Arg Gln Leu Gly Leu Gly Tyr Ala Asn His Gly Leu Gln Glu Thr Trp 460 465 470 475 tac tgg gac tct ggg aat ata aca gag gtg gtg atg agt gga gtg cgc 1671 Tyr Trp Asp Ser Gly Asn Ile Thr Glu Val Val Met Ser Gly Val Arg 480 485 490 tgc aca ggg act gag ctg tcc ctg gat cag tgt gcc cat cat ggc acc 1719 Cys Thr Gly Thr Glu Leu Ser Leu Asp Gln Cys Ala His His Gly Thr 495 500 505 cac atc acc tgc aag agg aca ggg acc cgc ttc act gct gga gtc atc 1767 His Ile Thr Cys Lys Arg Thr Gly Thr Arg Phe Thr Ala Gly Val Ile 510 515 520 tgt tct gag act gca tca gat ctg ttg ctg cac tca gca ctg gtg cag 1815 Cys Ser Glu Thr Ala Ser Asp Leu Leu Leu His Ser Ala Leu Val Gln 525 530 535 gag acc gcc tac atc gaa gac cgg ccc ctg cat atg ttg tac tgt gct 1863 Glu Thr Ala Tyr Ile Glu Asp Arg Pro Leu His Met Leu Tyr Cys Ala 540 545 550 555 gcg gaa gag aac tgc ctg gcc agc tca gcc cgc tca gcc aac tgg ccc 1911 Ala Glu Glu Asn Cys Leu Ala Ser Ser Ala Arg Ser Ala Asn Trp Pro 560 565 570 tat ggt cac cgg cgt ctg ctc cga ttc tcc tcc cag atc cac aac ctg 1959 Tyr Gly His Arg Arg Leu Leu Arg Phe Ser Ser Gln Ile His Asn Leu 575 580 585 gga cga gct gac ttc agg ccc aag gct ggg cgc cac tcc tgg gtg tgg 2007 Gly Arg Ala Asp Phe Arg Pro Lys Ala Gly Arg His Ser Trp Val Trp 590 595 600 cac gag tgc cat ggg cat tac cac agc atg gac ttc ttc act cac tat 2055 His Glu Cys His Gly His Tyr His Ser Met Asp Phe Phe Thr His Tyr 605 610 615 gat atc ctc acc cca aat ggc acc aag gtg gct gag ggc cac aaa gct 2103 Asp Ile Leu Thr Pro Asn Gly Thr Lys Val Ala Glu Gly His Lys Ala 620 625 630 635 agt ttc tgt ctc gaa gac act gag tgt cag gag gat gtc tcc aag cgg 2151 Ser Phe Cys Leu Glu Asp Thr Glu Cys Gln Glu Asp Val Ser Lys Arg 640 645 650 tat gag tgt gcc aac ttt gga gag caa ggc atc act gtg ggt tgc tgg 2199 Tyr Glu Cys Ala Asn Phe Gly Glu Gln Gly Ile Thr Val Gly Cys Trp 655 660 665 gat ctc tac cgg cat gac att gac tgt cag tgg att gac atc acg gat 2247 Asp Leu Tyr Arg His Asp Ile Asp Cys Gln Trp Ile Asp Ile Thr Asp 670 675 680 gtg aag cca gga aac tac att ctc cag gtt gtc atc aac cca aac ttt 2295 Val Lys Pro Gly Asn Tyr Ile Leu Gln Val Val Ile Asn Pro Asn Phe 685 690 695 gaa gta gca gag agt gac ttt acc aac aat gca atg aaa tgt aac tgc 2343 Glu Val Ala Glu Ser Asp Phe Thr Asn Asn Ala Met Lys Cys Asn Cys 700 705 710 715 aaa tat gat gga cat aga atc tgg gtg cac aac tgc cac att ggt gat 2391 Lys Tyr Asp Gly His Arg Ile Trp Val His Asn Cys His Ile Gly Asp 720 725 730 gcc ttc agt gaa gag gcc aac agg agg ttt gaa cgc tac cct ggc cag 2439 Ala Phe Ser Glu Glu Ala Asn Arg Arg Phe Glu Arg Tyr Pro Gly Gln 735 740 745 acc agc aac cag att atc taagtgccac tgccctctgc aaaccaccac 2487 Thr Ser Asn Gln Ile Ile 750 tggcccctaa tggcaggggt ctgaggctgc cattacctca ggagcttacc aagaaaccca 2547 tgtcagcaac cgcactcatc agaccatgca ctatggatgt ggaactgtca agcagaagtt 2607 ttcaccctcc ttcagaggcc agctgtcagt atctgtagcc aagcatggga atctttgctc 2667 ccaggcccag caccgagcag aacagaccag agcccaccac accacaaaga gcagcacctg 2727 actaactgcc cacaaaagat ggcagcagct cattttcttt aataggaggt caggatggtc 2787 agctccagta tctcccctaa gtttaggggg atacagcttt acctctagcc ttttggtggg 2847 ggaaaagatc cagccctccc acctcatttt ttactataat atgttgctag gtataatttt 2907 attttatata aaaagtgttt ctgtgattct tcagagccca ggagtcagtg ctggtggttg 2967 gagggacctg cccccactgg ttcatttaac cctctgtctc ggtgccctca gaacctcagc 3027 cagaaaggca aggaggaaat cagagcagga gcctcatact cttggtgatc tattcattct 3087 gtgacctcag gggtcacata taaggtcagt gtttctcgtc cccgccggat ctgcactgcc 3147 aactgggatt gggttcgaac agcttcataa acatcttcag cattttgtac catctgctcc 3207 ccaatggcca aaatcacatc accaggccgc agaccagccc ggtgtgcagg ggagcccagg 3267 atgactttat ggatgagtac accatgctga acatcgggaa agcttggttc tcgaagctgt 3327 agttcagcaa ggatgctggg actcagggtc agcatcatca ccccaatgta gcgccgctgg 3387 gacccactga ttccggagga ggaattcttc ttttccccac gatgcagaaa ctctcgaaga 3447 cgatcagaag ggatggcaaa ggagattcca gctgtgacct tcatggtgtt cactccaatc 3507 acctccccat ccaggttaac caggggacct ccagagtttc caaaatcaat agctgcatca 3567 gtttgaatgt attccacatt ggtttggggg agtcccaggt ctctggctgg acgctgagca 3627 gagctaacaa tgccggatgt gatcgtgttc tgcagtgcaa agggacttcc catggcaaca 3687 acaaactccc cttgccggac atcagctgag cgtcccagag gcagcgtggg gagaggctcc 3747 ttagtctgaa tcctcagcgt tgcgatgtct gccacgggat ccacagctgt gaccacggcc 3807 tcatacgtgt cgccgcttag cagtctcaca cggactctgc gccgatcagc caccacatgg 3867 gcgttggtga caatgagccc atcggcagcc accacgaatc ctgagccgtt cgagataggg 3927 acctcgcggc ccaagaaagg gtgccggtcc aggatctcga tatagaccac ggcaggtgct 3987 gtcttctcca ccacatctgc gatgaagttg tactgactcc ggggagaagc gggcggcggg 4047 ctagggacgg cggcgaggac ggccggagga ccccgacccc cgccccacaa caacaacagc 4107 actgcccccc cagcgcccag cgccaccgcc agccacgcgc gcgaacgggt tccagagttc 4167 tctgaggcct cccgggtcct ggtatctggg gtcaccgcag tcagttgtgc ccggggaccc 4227 ggggtcccag acgtcaggca tgctcggggt tcagtgaccc caacagacaa ccgggcccag 4287 agactggggg tcccataagt cactcgggcc cgggggtcag aagttcctga cgtcagcagg 4347 gcccggaggt caggggtcaa acggggtctc ctcccccagc gaatgccccc caaagcccgc 4407 catgcccgaa ggctccagcc tgcaccccgc cccgccctcg gcgcagccat cagctccgcc 4467 ttggctgcct cctcgcccgc cctactcaga ggcggcaccc aggacgcgag caggcggaca 4527 gtaggacgcg gggcacgccg gtacctgaag tccttcagaa gtgcacgccg ggaccaggat 4587 tccgggaggc cgactcctcc ctgccccacg aatgccggga attgtggtct ccgccggacg 4647 cgagttgtga gacggcccaa ggggccgcgg ggtatgctgg gaccgctagc ccttccggcg 4707 cgcctcagga cttcgggtcc cctcaccccg ggcggatgcc caaagactcc gccttcccaa 4767 gagcccctgc ggccgggcgc gaaaatggcg gcggcggcga cggccgggcg ctcctgaagc 4827 agcagttatg gagcttccct cagggccggg gccggagcgg ctctttgact cgcaccggta 4887 agagacccgg cgggaagaga ccgatccccg cgtgctctcg gccttcggcg cctgaccact 4947 tcgcctctcg cccccaggct tccgggtgac tgcttcctac tgctcgtgct gctgctctac 5007 gcgccagtcg ggttctgcct cctcgtcctg cgcctctttc tcgggatcca cg 5059 <210> SEQ ID NO 29 <211> LENGTH: 753 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 29 Met Arg Pro Val Ser Val Trp Gln Trp Ser Pro Trp Gly Leu Leu Leu 1 5 10 15 Cys Leu Leu Cys Ser Ser Cys Leu Gly Ser Pro Ser Pro Ser Thr Gly 20 25 30 Pro Glu Lys Lys Ala Gly Ser Gln Gly Leu Arg Phe Arg Leu Ala Gly 35 40 45 Phe Pro Arg Lys Pro Tyr Glu Gly Arg Val Glu Ile Gln Arg Ala Gly 50 55 60 Glu Trp Gly Thr Ile Cys Asp Asp Asp Phe Thr Leu Gln Ala Ala His 65 70 75 80 Ile Leu Cys Arg Glu Leu Gly Phe Thr Glu Ala Thr Gly Trp Thr His 85 90 95 Ser Ala Lys Tyr Gly Pro Gly Thr Gly Arg Ile Trp Leu Asp Asn Leu 100 105 110 Ser Cys Ser Gly Thr Glu Gln Ser Val Thr Glu Cys Ala Ser Arg Gly 115 120 125 Trp Gly Asn Ser Asp Cys Thr His Asp Glu Asp Ala Gly Val Ile Cys 130 135 140 Lys Asp Gln Arg Leu Pro Gly Phe Ser Asp Ser Asn Val Ile Glu Val 145 150 155 160 Glu His His Leu Gln Val Glu Glu Val Arg Ile Arg Pro Ala Val Gly 165 170 175 Trp Gly Arg Arg Pro Leu Pro Val Thr Glu Gly Leu Val Glu Val Arg 180 185 190 Leu Pro Asp Gly Trp Ser Gln Val Cys Asp Lys Gly Trp Ser Ala His 195 200 205 Asn Ser His Val Val Cys Gly Met Leu Gly Phe Pro Ser Glu Lys Arg 210 215 220 Val Asn Ala Ala Phe Tyr Arg Leu Leu Ala Gln Arg Gln Gln His Ser 225 230 235 240 Phe Gly Leu His Gly Val Ala Cys Val Gly Thr Glu Ala His Leu Ser 245 250 255 Leu Cys Ser Leu Glu Phe Tyr Arg Ala Asn Asp Thr Ala Arg Cys Pro 260 265 270 Gly Gly Gly Pro Ala Val Val Ser Cys Val Pro Gly Pro Val Tyr Ala 275 280 285 Ala Ser Ser Gly Gln Lys Lys Gln Gln Gln Ser Lys Pro Gln Gly Glu 290 295 300 Val Arg Val Arg Leu Lys Gly Gly Ala His Pro Gly Glu Gly Arg Val 305 310 315 320 Glu Val Leu Lys Ala Ser Thr Trp Gly Thr Val Cys Tyr Arg Lys Trp 325 330 335 Asp Leu His Ala Ala Ser Val Val Cys Arg Glu Leu Gly Phe Gly Ser 340 345 350 Ala Arg Glu Ala Leu Ser Gly Ala Arg Met Gly Gln Gly Met Gly Ala 355 360 365 Ile His Leu Ser Glu Val Arg Cys Ser Gly Gln Glu Leu Ser Leu Trp 370 375 380 Lys Cys Pro His Lys Asn Ile Thr Ala Glu Asp Cys Ser His Ser Gln 385 390 395 400 Asp Ala Gly Val Arg Cys Asn Leu Pro Tyr Thr Gly Ala Glu Thr Arg 405 410 415 Ile Arg Leu Ser Gly Gly Arg Ser Gln His Glu Gly Arg Val Glu Val 420 425 430 Gln Ile Gly Gly Pro Gly Pro Leu Arg Trp Gly Leu Ile Cys Gly Asp 435 440 445 Asp Trp Gly Thr Leu Glu Ala Met Val Ala Cys Arg Gln Leu Gly Leu 450 455 460 Gly Tyr Ala Asn His Gly Leu Gln Glu Thr Trp Tyr Trp Asp Ser Gly 465 470 475 480 Asn Ile Thr Glu Val Val Met Ser Gly Val Arg Cys Thr Gly Thr Glu 485 490 495 Leu Ser Leu Asp Gln Cys Ala His His Gly Thr His Ile Thr Cys Lys 500 505 510 Arg Thr Gly Thr Arg Phe Thr Ala Gly Val Ile Cys Ser Glu Thr Ala 515 520 525 Ser Asp Leu Leu Leu His Ser Ala Leu Val Gln Glu Thr Ala Tyr Ile 530 535 540 Glu Asp Arg Pro Leu His Met Leu Tyr Cys Ala Ala Glu Glu Asn Cys 545 550 555 560 Leu Ala Ser Ser Ala Arg Ser Ala Asn Trp Pro Tyr Gly His Arg Arg 565 570 575 Leu Leu Arg Phe Ser Ser Gln Ile His Asn Leu Gly Arg Ala Asp Phe 580 585 590 Arg Pro Lys Ala Gly Arg His Ser Trp Val Trp His Glu Cys His Gly 595 600 605 His Tyr His Ser Met Asp Phe Phe Thr His Tyr Asp Ile Leu Thr Pro 610 615 620 Asn Gly Thr Lys Val Ala Glu Gly His Lys Ala Ser Phe Cys Leu Glu 625 630 635 640 Asp Thr Glu Cys Gln Glu Asp Val Ser Lys Arg Tyr Glu Cys Ala Asn 645 650 655 Phe Gly Glu Gln Gly Ile Thr Val Gly Cys Trp Asp Leu Tyr Arg His 660 665 670 Asp Ile Asp Cys Gln Trp Ile Asp Ile Thr Asp Val Lys Pro Gly Asn 675 680 685 Tyr Ile Leu Gln Val Val Ile Asn Pro Asn Phe Glu Val Ala Glu Ser 690 695 700 Asp Phe Thr Asn Asn Ala Met Lys Cys Asn Cys Lys Tyr Asp Gly His 705 710 715 720 Arg Ile Trp Val His Asn Cys His Ile Gly Asp Ala Phe Ser Glu Glu 725 730 735 Ala Asn Arg Arg Phe Glu Arg Tyr Pro Gly Gln Thr Ser Asn Gln Ile 740 745 750 Ile <210> SEQ ID NO 30 <211> LENGTH: 4552 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (127)..(1950) <400> SEQUENCE: 30 gggagagagg ggggtccagt ctcccctggc cgagcatttt ttttttggaa gtcctaggac 60 taatctccag gaccagcact cttctcccag cccttagggt cctgctcggc caaggccttc 120 cctgcc atg cga cct gtc agt gtc tgg cag tgg agc ccc tgg ggg ctg 168 Met Arg Pro Val Ser Val Trp Gln Trp Ser Pro Trp Gly Leu 1 5 10 ctg ctg tgc ctg ctg tgc agt tcg tgc ttg ggg tct cca tcc cct tcc 216 Leu Leu Cys Leu Leu Cys Ser Ser Cys Leu Gly Ser Pro Ser Pro Ser 15 20 25 30 acg ggc cct gag aag aag gcc ggg agc cag ggg ctt cgg ttc cgg ctg 264 Thr Gly Pro Glu Lys Lys Ala Gly Ser Gln Gly Leu Arg Phe Arg Leu 35 40 45 gct ggc ttc ccc agg aag ccc tac gag ggc cgc gtg gag ata cag cga 312 Ala Gly Phe Pro Arg Lys Pro Tyr Glu Gly Arg Val Glu Ile Gln Arg 50 55 60 gct ggt gaa tgg ggc acc atc tgc gat gat gac ttc acg ctg cag gct 360 Ala Gly Glu Trp Gly Thr Ile Cys Asp Asp Asp Phe Thr Leu Gln Ala 65 70 75 gcc cac atc ctc tgc cgg gag ctg ggc ttc aca gag gcc aca ggc tgg 408 Ala His Ile Leu Cys Arg Glu Leu Gly Phe Thr Glu Ala Thr Gly Trp 80 85 90 acc cac agt gcc aaa tat ggc cct gga aca ggc cgc atc tgg ctg gac 456 Thr His Ser Ala Lys Tyr Gly Pro Gly Thr Gly Arg Ile Trp Leu Asp 95 100 105 110 aac ttg agc tgc agt ggg acc gag cag agt gtg act gaa tgt gcc tcc 504 Asn Leu Ser Cys Ser Gly Thr Glu Gln Ser Val Thr Glu Cys Ala Ser 115 120 125 cgg ggc tgg ggg aac agt gac tgt acg cac gat gag gat gct ggg gtc 552 Arg Gly Trp Gly Asn Ser Asp Cys Thr His Asp Glu Asp Ala Gly Val 130 135 140 atc tgc aaa gac cag cgc ctc cct ggc ttc tcg gac tcc aat gtc att 600 Ile Cys Lys Asp Gln Arg Leu Pro Gly Phe Ser Asp Ser Asn Val Ile 145 150 155 gag gcc cgt gtc cgt cta aag ggc ggc gcc cac cct gga gag ggc cgg 648 Glu Ala Arg Val Arg Leu Lys Gly Gly Ala His Pro Gly Glu Gly Arg 160 165 170 gta gaa gtc ctg aag gcc agc aca tgg ggc aca gtc tgt gac cgc aag 696 Val Glu Val Leu Lys Ala Ser Thr Trp Gly Thr Val Cys Asp Arg Lys 175 180 185 190 tgg gac ctg cat gca gcc agc gtg gtg tgt cgg gag ctg ggc ttc ggg 744 Trp Asp Leu His Ala Ala Ser Val Val Cys Arg Glu Leu Gly Phe Gly 195 200 205 agt gct cga gaa gct ctg agt ggc gct cgc atg ggg cag ggc atg ggt 792 Ser Ala Arg Glu Ala Leu Ser Gly Ala Arg Met Gly Gln Gly Met Gly 210 215 220 gct atc cac ctg agt gaa gtt cgc tgc tct gga cag gag ctc tcc ctc 840 Ala Ile His Leu Ser Glu Val Arg Cys Ser Gly Gln Glu Leu Ser Leu 225 230 235 tgg aag tgc ccc cac aag aac atc aca gct gag gat tgt tca cat agc 888 Trp Lys Cys Pro His Lys Asn Ile Thr Ala Glu Asp Cys Ser His Ser 240 245 250 cag gat gcc ggg gtc cgg tgc aac cta cct tac act ggg gca gag acc 936 Gln Asp Ala Gly Val Arg Cys Asn Leu Pro Tyr Thr Gly Ala Glu Thr 255 260 265 270 agg atc cga ctc agt ggg ggc cgc agc caa cat gag ggg cga gtc gag 984 Arg Ile Arg Leu Ser Gly Gly Arg Ser Gln His Glu Gly Arg Val Glu 275 280 285 gtg caa ata ggg gga cct ggg ccc ctt cgc tgg ggc ctc atc tgt ggg 1032 Val Gln Ile Gly Gly Pro Gly Pro Leu Arg Trp Gly Leu Ile Cys Gly 290 295 300 gat gac tgg ggg acc ctg gag gcc atg gtg gcc tgt agg caa ctg ggt 1080 Asp Asp Trp Gly Thr Leu Glu Ala Met Val Ala Cys Arg Gln Leu Gly 305 310 315 ctg ggc tac gcc aac cac ggc ctg cag gag acc tgg tac tgg gac tct 1128 Leu Gly Tyr Ala Asn His Gly Leu Gln Glu Thr Trp Tyr Trp Asp Ser 320 325 330 ggg aat ata aca gag gtg gtg atg agt gga gtg cgc tgc aca ggg act 1176 Gly Asn Ile Thr Glu Val Val Met Ser Gly Val Arg Cys Thr Gly Thr 335 340 345 350 gag ctg tcc ctg gat cag tgt gcc cat cat ggc acc cac atc acc tgc 1224 Glu Leu Ser Leu Asp Gln Cys Ala His His Gly Thr His Ile Thr Cys 355 360 365 aag agg aca ggg acc cgc ttc act gct gga gtc atc tgt tct gag act 1272 Lys Arg Thr Gly Thr Arg Phe Thr Ala Gly Val Ile Cys Ser Glu Thr 370 375 380 gca tca gat ctg ttg ctg cac tca gca ctg gtg cag gag acc gcc tac 1320 Ala Ser Asp Leu Leu Leu His Ser Ala Leu Val Gln Glu Thr Ala Tyr 385 390 395 atc gaa gac cgg ccc ctg cat atg ttg tac tgt gct gcg gaa gag aac 1368 Ile Glu Asp Arg Pro Leu His Met Leu Tyr Cys Ala Ala Glu Glu Asn 400 405 410 tgc ctg gcc agc tca gcc cgc tca gcc aac tgg ccc tat ggt cac cgg 1416 Cys Leu Ala Ser Ser Ala Arg Ser Ala Asn Trp Pro Tyr Gly His Arg 415 420 425 430 cgt ctg ctc cga ttc tcc tcc cag atc cac aac ctg gga cga gct gac 1464 Arg Leu Leu Arg Phe Ser Ser Gln Ile His Asn Leu Gly Arg Ala Asp 435 440 445 ttc agg ccc aag gct ggg cgc cac tcc tgg gtg tgg cac gag tgc cat 1512 Phe Arg Pro Lys Ala Gly Arg His Ser Trp Val Trp His Glu Cys His 450 455 460 ggg cat tac cac agc atg gac ttc ttc act cac tat gat atc ctc acc 1560 Gly His Tyr His Ser Met Asp Phe Phe Thr His Tyr Asp Ile Leu Thr 465 470 475 cca aat ggc acc aag gtg gct gag ggc cac aaa gct agt ttc tgt ctc 1608 Pro Asn Gly Thr Lys Val Ala Glu Gly His Lys Ala Ser Phe Cys Leu 480 485 490 gaa gac act gag tgt cag gag gat gtc tcc aag cgg tat gag tgt gcc 1656 Glu Asp Thr Glu Cys Gln Glu Asp Val Ser Lys Arg Tyr Glu Cys Ala 495 500 505 510 aac ttt gga gag caa ggc atc act gtg ggt tgc tgg gat ctc tac cgg 1704 Asn Phe Gly Glu Gln Gly Ile Thr Val Gly Cys Trp Asp Leu Tyr Arg 515 520 525 cat gac att gac tgt cag tgg att gac atc acg gat gtg aag cca gga 1752 His Asp Ile Asp Cys Gln Trp Ile Asp Ile Thr Asp Val Lys Pro Gly 530 535 540 aac tac att ctc cag gtt gtc atc aac cca aac ttt gaa gta gca gag 1800 Asn Tyr Ile Leu Gln Val Val Ile Asn Pro Asn Phe Glu Val Ala Glu 545 550 555 agt gac ttt acc aac aat gca atg aaa tgt aac tgc aaa tat gat gga 1848 Ser Asp Phe Thr Asn Asn Ala Met Lys Cys Asn Cys Lys Tyr Asp Gly 560 565 570 cat aga atc tgg gtg cac aac tgc cac att ggt gat gcc ttc agt gaa 1896 His Arg Ile Trp Val His Asn Cys His Ile Gly Asp Ala Phe Ser Glu 575 580 585 590 gag gcc aac agg agg ttt gaa cgc tac cct ggc cag acc agc aac cag 1944 Glu Ala Asn Arg Arg Phe Glu Arg Tyr Pro Gly Gln Thr Ser Asn Gln 595 600 605 att atc taagtgccac tgccctctgc aaaccaccac tggcccctaa tggcaggggt 2000 Ile Ile ctgaggctgc cattacctca ggagcttacc aagaaaccca tgtcagcaac cgcactcatc 2060 agaccatgca ctatggatgt ggaactgtca agcagaagtt ttcaccctcc ttcagaggcc 2120 agctgtcagt atctgtagcc aagcatggga atctttgctc ccaggcccag caccgagcag 2180 aacagaccag agcccaccac accacaaaga gcagcacctg actaactgcc cacaaaagat 2240 ggcagcagct cattttcttt aataggaggt caggatggtc agctccagta tctcccctaa 2300 gtttaggggg atacagcttt acctctagcc ttttggtggg ggaaaagatc cagccctccc 2360 acctcatttt ttactataat atgttgctag gtataatttt attttatata aaaagtgttt 2420 ctgtgattct tcagagccca ggagtcagtg ctggtggttg gagggacctg cccccactgg 2480 ttcatttaac cctctgtctc ggtgccctca gaacctcagc cagaaaggca aggaggaaat 2540 cagagcagga gcctcatact cttggtgatc tattcattct gtgacctcag gggtcacata 2600 taaggtcagt gtttctcgtc cccgccggat ctgcactgcc aactgggatt gggttcgaac 2660 agcttcataa acatcttcag cattttgtac catctgctcc ccaatggcca aaatcacatc 2720 accaggccgc agaccagccc ggtgtgcagg ggagcccagg atgactttat ggatgagtac 2780 accatgctga acatcgggaa agcttggttc tcgaagctgt agttcagcaa ggatgctggg 2840 actcagggtc agcatcatca ccccaatgta gcgccgctgg gacccactga ttccggagga 2900 ggaattcttc ttttccccac gatgcagaaa ctctcgaaga cgatcagaag ggatggcaaa 2960 ggagattcca gctgtgacct tcatggtgtt cactccaatc acctccccat ccaggttaac 3020 caggggacct ccagagtttc caaaatcaat agctgcatca gtttgaatgt attccacatt 3080 ggtttggggg agtcccaggt ctctggctgg acgctgagca gagctaacaa tgccggatgt 3140 gatcgtgttc tgcagtgcaa agggacttcc catggcaaca acaaactccc cttgccggac 3200 atcagctgag cgtcccagag gcagcgtggg gagaggctcc ttagtctgaa tcctcagcgt 3260 tgcgatgtct gccacgggat ccacagctgt gaccacggcc tcatacgtgt cgccgcttag 3320 cagtctcaca cggactctgc gccgatcagc caccacatgg gcgttggtga caatgagccc 3380 atcggcagcc accacgaatc ctgagccgtt cgagataggg acctcgcggc ccaagaaagg 3440 gtgccggtcc aggatctcga tatagaccac ggcaggtgct gtcttctcca ccacatctgc 3500 gatgaagttg tactgactcc ggggagaagc gggcggcggg ctagggacgg cggcgaggac 3560 ggccggagga ccccgacccc cgccccacaa caacaacagc actgcccccc cagcgcccag 3620 cgccaccgcc agccacgcgc gcgaacgggt tccagagttc tctgaggcct cccgggtcct 3680 ggtatctggg gtcaccgcag tcagttgtgc ccggggaccc ggggtcccag acgtcaggca 3740 tgctcggggt tcagtgaccc caacagacaa ccgggcccag agactggggg tcccataagt 3800 cactcgggcc cgggggtcag aagttcctga cgtcagcagg gcccggaggt caggggtcaa 3860 acggggtctc ctcccccagc gaatgccccc caaagcccgc catgcccgaa ggctccagcc 3920 tgcaccccgc cccgccctcg gcgcagccat cagctccgcc ttggctgcct cctcgcccgc 3980 cctactcaga ggcggcaccc aggacgcgag caggcggaca gtaggacgcg gggcacgccg 4040 gtacctgaag tccttcagaa gtgcacgccg ggaccaggat tccgggaggc cgactcctcc 4100 ctgccccacg aatgccggga attgtggtct ccgccggacg cgagttgtga gacggcccaa 4160 ggggccgcgg ggtatgctgg gaccgctagc ccttccggcg cgcctcagga cttcgggtcc 4220 cctcaccccg ggcggatgcc caaagactcc gccttcccaa gagcccctgc ggccgggcgc 4280 gaaaatggcg gcggcggcga cggccgggcg ctcctgaagc agcagttatg gagcttccct 4340 cagggccggg gccggagcgg ctctttgact cgcaccggta agagacccgg cgggaagaga 4400 ccgatccccg cgtgctctcg gccttcggcg cctgaccact tcgcctctcg cccccaggct 4460 tccgggtgac tgcttcctac tgctcgtgct gctgctctac gcgccagtcg ggttctgcct 4520 cctcgtcctg cgcctctttc tcgggatcca cg 4552 <210> SEQ ID NO 31 <211> LENGTH: 608 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 31 Met Arg Pro Val Ser Val Trp Gln Trp Ser Pro Trp Gly Leu Leu Leu 1 5 10 15 Cys Leu Leu Cys Ser Ser Cys Leu Gly Ser Pro Ser Pro Ser Thr Gly 20 25 30 Pro Glu Lys Lys Ala Gly Ser Gln Gly Leu Arg Phe Arg Leu Ala Gly 35 40 45 Phe Pro Arg Lys Pro Tyr Glu Gly Arg Val Glu Ile Gln Arg Ala Gly 50 55 60 Glu Trp Gly Thr Ile Cys Asp Asp Asp Phe Thr Leu Gln Ala Ala His 65 70 75 80 Ile Leu Cys Arg Glu Leu Gly Phe Thr Glu Ala Thr Gly Trp Thr His 85 90 95 Ser Ala Lys Tyr Gly Pro Gly Thr Gly Arg Ile Trp Leu Asp Asn Leu 100 105 110 Ser Cys Ser Gly Thr Glu Gln Ser Val Thr Glu Cys Ala Ser Arg Gly 115 120 125 Trp Gly Asn Ser Asp Cys Thr His Asp Glu Asp Ala Gly Val Ile Cys 130 135 140 Lys Asp Gln Arg Leu Pro Gly Phe Ser Asp Ser Asn Val Ile Glu Ala 145 150 155 160 Arg Val Arg Leu Lys Gly Gly Ala His Pro Gly Glu Gly Arg Val Glu 165 170 175 Val Leu Lys Ala Ser Thr Trp Gly Thr Val Cys Asp Arg Lys Trp Asp 180 185 190 Leu His Ala Ala Ser Val Val Cys Arg Glu Leu Gly Phe Gly Ser Ala 195 200 205 Arg Glu Ala Leu Ser Gly Ala Arg Met Gly Gln Gly Met Gly Ala Ile 210 215 220 His Leu Ser Glu Val Arg Cys Ser Gly Gln Glu Leu Ser Leu Trp Lys 225 230 235 240 Cys Pro His Lys Asn Ile Thr Ala Glu Asp Cys Ser His Ser Gln Asp 245 250 255 Ala Gly Val Arg Cys Asn Leu Pro Tyr Thr Gly Ala Glu Thr Arg Ile 260 265 270 Arg Leu Ser Gly Gly Arg Ser Gln His Glu Gly Arg Val Glu Val Gln 275 280 285 Ile Gly Gly Pro Gly Pro Leu Arg Trp Gly Leu Ile Cys Gly Asp Asp 290 295 300 Trp Gly Thr Leu Glu Ala Met Val Ala Cys Arg Gln Leu Gly Leu Gly 305 310 315 320 Tyr Ala Asn His Gly Leu Gln Glu Thr Trp Tyr Trp Asp Ser Gly Asn 325 330 335 Ile Thr Glu Val Val Met Ser Gly Val Arg Cys Thr Gly Thr Glu Leu 340 345 350 Ser Leu Asp Gln Cys Ala His His Gly Thr His Ile Thr Cys Lys Arg 355 360 365 Thr Gly Thr Arg Phe Thr Ala Gly Val Ile Cys Ser Glu Thr Ala Ser 370 375 380 Asp Leu Leu Leu His Ser Ala Leu Val Gln Glu Thr Ala Tyr Ile Glu 385 390 395 400 Asp Arg Pro Leu His Met Leu Tyr Cys Ala Ala Glu Glu Asn Cys Leu 405 410 415 Ala Ser Ser Ala Arg Ser Ala Asn Trp Pro Tyr Gly His Arg Arg Leu 420 425 430 Leu Arg Phe Ser Ser Gln Ile His Asn Leu Gly Arg Ala Asp Phe Arg 435 440 445 Pro Lys Ala Gly Arg His Ser Trp Val Trp His Glu Cys His Gly His 450 455 460 Tyr His Ser Met Asp Phe Phe Thr His Tyr Asp Ile Leu Thr Pro Asn 465 470 475 480 Gly Thr Lys Val Ala Glu Gly His Lys Ala Ser Phe Cys Leu Glu Asp 485 490 495 Thr Glu Cys Gln Glu Asp Val Ser Lys Arg Tyr Glu Cys Ala Asn Phe 500 505 510 Gly Glu Gln Gly Ile Thr Val Gly Cys Trp Asp Leu Tyr Arg His Asp 515 520 525 Ile Asp Cys Gln Trp Ile Asp Ile Thr Asp Val Lys Pro Gly Asn Tyr 530 535 540 Ile Leu Gln Val Val Ile Asn Pro Asn Phe Glu Val Ala Glu Ser Asp 545 550 555 560 Phe Thr Asn Asn Ala Met Lys Cys Asn Cys Lys Tyr Asp Gly His Arg 565 570 575 Ile Trp Val His Asn Cys His Ile Gly Asp Ala Phe Ser Glu Glu Ala 580 585 590 Asn Arg Arg Phe Glu Arg Tyr Pro Gly Gln Thr Ser Asn Gln Ile Ile 595 600 605 <210> SEQ ID NO 32 <211> LENGTH: 16545 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (862)..(14769) <400> SEQUENCE: 32 aaagacagaa ccccagagaa aaacgctgcc aattcgttgc tttattgttc cctgcctggg 60 gacctcaata gccttttcca ttaaccttcc cttcttacgc aacggttaat gactttgggg 120 gttgttttgc tttctgtttc tgctgagtca ctaaattttg cctctttgtc cccaggtgct 180 gctcagcata aaagttaaaa gtgcaattca ggaagtactg ggattctgtg tagagccgag 240 gaaaccattt ccctaagaga agctctgttc cttggcttgt ccttccttcc cgggaaggaa 300 gcttccgagg aacgaaggga gaagctttgt tttgcctgca gaagcagccc tgtgctcggc 360 tgagggttct cagctggctg tgaactgcgg agcattgtag gcgcctggct ggctcaggcc 420 aatgcagaag tctctccctt ctccaaagac ccaaatcccc acagaaccag cttcgagtta 480 ctttcccttc aaggggatta aaataattgt gatttgtggc gctctccgtt cgcggtggta 540 ttttcctgtt gtgttaaatg cctcttatta agtaatagat gtgatttatg tgaacgacga 600 aggggtgtgt ggtggattcg gtgattaatc agtgaattcc catccgctgg catctctcac 660 tgcccctctt gcgtgatgta agatcagacg taccctgcat tgaaaagtca agacacacgg 720 gcgtctcgct cgcgctcaca cacgctctgc ctcctctctc cagcacgcgc gcatccctcc 780 accttccaca tcctgctcca ggcaggagaa ggctgactgg ctggactcat tgagctgaag 840 aatttccagt gacatttgta a atg acg ccg ctc ggt tcc agg ctc caa gcg 891 Met Thr Pro Leu Gly Ser Arg Leu Gln Ala 1 5 10 gcc cct gcc gcc gcc gcc gcc gcc ggg ccg aag gtg ccg ccg agc agt 939 Ala Pro Ala Ala Ala Ala Ala Ala Gly Pro Lys Val Pro Pro Ser Ser 15 20 25 ctc cag cgc agg ctt cct tac cgg gcg acc aca atg tcc gag ttt ctc 987 Leu Gln Arg Arg Leu Pro Tyr Arg Ala Thr Thr Met Ser Glu Phe Leu 30 35 40 ctc gcc tta ctc act ctc tcg gga tta ttg ccg att gcc agg gtg ctg 1035 Leu Ala Leu Leu Thr Leu Ser Gly Leu Leu Pro Ile Ala Arg Val Leu 45 50 55 acc gtg gga gcc gac cga gat cag cag ttg tgt gat cct ggt gaa ttt 1083 Thr Val Gly Ala Asp Arg Asp Gln Gln Leu Cys Asp Pro Gly Glu Phe 60 65 70 ctt tgc cac gat cac gtg act tgt gtc tcc cgg agc tgg ctg tgt gat 1131 Leu Cys His Asp His Val Thr Cys Val Ser Arg Ser Trp Leu Cys Asp 75 80 85 90 ggg gac cct gac tgc cct gat gat tca gac gag tct tta gat acc tgt 1179 Gly Asp Pro Asp Cys Pro Asp Asp Ser Asp Glu Ser Leu Asp Thr Cys 95 100 105 ccc gag gag gta gaa atc aag tgc ccc ttg aat cac att gct tgc ctt 1227 Pro Glu Glu Val Glu Ile Lys Cys Pro Leu Asn His Ile Ala Cys Leu 110 115 120 ggt acc aac aaa tgt gtt cat tta tcc cag ctg tgc aat ggt gtc ttg 1275 Gly Thr Asn Lys Cys Val His Leu Ser Gln Leu Cys Asn Gly Val Leu 125 130 135 gac tgc cca gat ggg tat gac gaa gga gta cat tgt cag gaa ctg tta 1323 Asp Cys Pro Asp Gly Tyr Asp Glu Gly Val His Cys Gln Glu Leu Leu 140 145 150 tcc aat tgc caa cag ctg aat tgt cag tat aaa tgt aca atg gtc aga 1371 Ser Asn Cys Gln Gln Leu Asn Cys Gln Tyr Lys Cys Thr Met Val Arg 155 160 165 170 aat agt aca aga tgt tac tgt gag gat gga ttc gaa ata aca gaa gat 1419 Asn Ser Thr Arg Cys Tyr Cys Glu Asp Gly Phe Glu Ile Thr Glu Asp 175 180 185 ggg aga agc tgt aaa gat caa gat gaa tgt gct gtt tat ggt aca tgc 1467 Gly Arg Ser Cys Lys Asp Gln Asp Glu Cys Ala Val Tyr Gly Thr Cys 190 195 200 agc cag acc tgc aga aac aca cat gga tcc tac act tgc agt tgt gtg 1515 Ser Gln Thr Cys Arg Asn Thr His Gly Ser Tyr Thr Cys Ser Cys Val 205 210 215 gaa ggc tac cta atg cag cca gac aac aga tct tgc aag gct aaa att 1563 Glu Gly Tyr Leu Met Gln Pro Asp Asn Arg Ser Cys Lys Ala Lys Ile 220 225 230 gaa cct aca gat aga cca cct ata cta tta att gca aat ttt gaa aca 1611 Glu Pro Thr Asp Arg Pro Pro Ile Leu Leu Ile Ala Asn Phe Glu Thr 235 240 245 250 att gag gtt ttc tat ctt aat gga agt aaa atg gca act cta agc tca 1659 Ile Glu Val Phe Tyr Leu Asn Gly Ser Lys Met Ala Thr Leu Ser Ser 255 260 265 gtc aat gga aat gaa att cat act ctg gat ttt att tat aat gaa gat 1707 Val Asn Gly Asn Glu Ile His Thr Leu Asp Phe Ile Tyr Asn Glu Asp 270 275 280 gtg att tgt tgg att gaa tca aga gaa tct tca aat caa ctc aaa tgt 1755 Val Ile Cys Trp Ile Glu Ser Arg Glu Ser Ser Asn Gln Leu Lys Cys 285 290 295 atc cag ata aca aaa gca gga gga tta aca gat gaa tgg aca atc aat 1803 Ile Gln Ile Thr Lys Ala Gly Gly Leu Thr Asp Glu Trp Thr Ile Asn 300 305 310 att ctt caa tcc ttc cac aat gtg caa caa atg gcg att gac tgg ctc 1851 Ile Leu Gln Ser Phe His Asn Val Gln Gln Met Ala Ile Asp Trp Leu 315 320 325 330 act cga aat ctc tat ttt gtg gac cat gtc ggt gac cgg atc ttt gtt 1899 Thr Arg Asn Leu Tyr Phe Val Asp His Val Gly Asp Arg Ile Phe Val 335 340 345 tgt aat tcc aac ggt tct gta tgt gtc acc ctg att gat ctg gag ctt 1947 Cys Asn Ser Asn Gly Ser Val Cys Val Thr Leu Ile Asp Leu Glu Leu 350 355 360 cac aat cct aaa gca ata gca gta gat cca ata gca gga aaa ctt ttc 1995 His Asn Pro Lys Ala Ile Ala Val Asp Pro Ile Ala Gly Lys Leu Phe 365 370 375 ttt act gac tac ggg aat gtc gcc aaa gtg gag aga tgt gac atg gat 2043 Phe Thr Asp Tyr Gly Asn Val Ala Lys Val Glu Arg Cys Asp Met Asp 380 385 390 ggg atg aac cga aca agg ata att gat tca aag aca gag cag cca gct 2091 Gly Met Asn Arg Thr Arg Ile Ile Asp Ser Lys Thr Glu Gln Pro Ala 395 400 405 410 gca ctg gca cta gac cta gtc aac aaa ttg gtt tac tgg gta gat ctt 2139 Ala Leu Ala Leu Asp Leu Val Asn Lys Leu Val Tyr Trp Val Asp Leu 415 420 425 tac ttg gac tat gtg gga gta gtg gac tat caa gga aaa aat aga cac 2187 Tyr Leu Asp Tyr Val Gly Val Val Asp Tyr Gln Gly Lys Asn Arg His 430 435 440 act gtc att caa ggc aga caa gtc aga cat ctt tat ggt ata act gtg 2235 Thr Val Ile Gln Gly Arg Gln Val Arg His Leu Tyr Gly Ile Thr Val 445 450 455 ttt gaa gat tat ttg tat gca acc aat tct gat aac tac aat atc gta 2283 Phe Glu Asp Tyr Leu Tyr Ala Thr Asn Ser Asp Asn Tyr Asn Ile Val 460 465 470 agg ata aac cga ttt aat ggg act gat att cac tca tta att aaa att 2331 Arg Ile Asn Arg Phe Asn Gly Thr Asp Ile His Ser Leu Ile Lys Ile 475 480 485 490 gag aat gct tgg gga atc cga att tat caa aaa aga act caa cca aca 2379 Glu Asn Ala Trp Gly Ile Arg Ile Tyr Gln Lys Arg Thr Gln Pro Thr 495 500 505 gtc aga agc cat gca tgt gaa gtc gat cca tat gga atg cca ggg ggc 2427 Val Arg Ser His Ala Cys Glu Val Asp Pro Tyr Gly Met Pro Gly Gly 510 515 520 tgt tca cac atc tgt cta ctc agc agc agt tac aaa act cgg act tgt 2475 Cys Ser His Ile Cys Leu Leu Ser Ser Ser Tyr Lys Thr Arg Thr Cys 525 530 535 cgc tgc agg act ggc ttc aac ttg gga agt gat ggc agg tca tgc aaa 2523 Arg Cys Arg Thr Gly Phe Asn Leu Gly Ser Asp Gly Arg Ser Cys Lys 540 545 550 aga cca aag aat gag ttg ttc ctc ttt tat ggg aaa gga cgc cca gga 2571 Arg Pro Lys Asn Glu Leu Phe Leu Phe Tyr Gly Lys Gly Arg Pro Gly 555 560 565 570 att gtt aga gga atg gac ttg aat acc aag ata gct gat gaa tac atg 2619 Ile Val Arg Gly Met Asp Leu Asn Thr Lys Ile Ala Asp Glu Tyr Met 575 580 585 atc ccc ata gaa aat ctg gta aac cct cgt gct tta gac ttt cac gca 2667 Ile Pro Ile Glu Asn Leu Val Asn Pro Arg Ala Leu Asp Phe His Ala 590 595 600 gaa acc aat tac atc tac ttt gct gac acc acc agt ttc cta att ggc 2715 Glu Thr Asn Tyr Ile Tyr Phe Ala Asp Thr Thr Ser Phe Leu Ile Gly 605 610 615 cgg cag aag ata gat ggc aca gag aga gaa acc atc ctg aaa gat gat 2763 Arg Gln Lys Ile Asp Gly Thr Glu Arg Glu Thr Ile Leu Lys Asp Asp 620 625 630 ctg gat aat gta gag ggc att gct gtg gac tgg att gga aat aat ctt 2811 Leu Asp Asn Val Glu Gly Ile Ala Val Asp Trp Ile Gly Asn Asn Leu 635 640 645 650 tac tgg acc aat gat ggc cat agg aaa acc att aat gtg gct agg ctg 2859 Tyr Trp Thr Asn Asp Gly His Arg Lys Thr Ile Asn Val Ala Arg Leu 655 660 665 gaa aaa gct tct cag agt cgg aag act ctt tta gag ggt gaa atg tct 2907 Glu Lys Ala Ser Gln Ser Arg Lys Thr Leu Leu Glu Gly Glu Met Ser 670 675 680 cat ccc aga gga att gtg gtg gat cca att aat ggt tgg atg tat tgg 2955 His Pro Arg Gly Ile Val Val Asp Pro Ile Asn Gly Trp Met Tyr Trp 685 690 695 aca gac tgg gag gaa gat gaa ata gat gac agc gtg gga agg att gag 3003 Thr Asp Trp Glu Glu Asp Glu Ile Asp Asp Ser Val Gly Arg Ile Glu 700 705 710 aag gcc tgg atg gat gga ttc aat cgg cag att ttt gtg act tca aag 3051 Lys Ala Trp Met Asp Gly Phe Asn Arg Gln Ile Phe Val Thr Ser Lys 715 720 725 730 atg ctg tgg cca aac ggt tta act ctg gac ttt cac acc aac aca tta 3099 Met Leu Trp Pro Asn Gly Leu Thr Leu Asp Phe His Thr Asn Thr Leu 735 740 745 tac tgg tgt gat gcc tat tac gat cat att gaa aaa gta ttt ttg aat 3147 Tyr Trp Cys Asp Ala Tyr Tyr Asp His Ile Glu Lys Val Phe Leu Asn 750 755 760 ggg act cac agg aag att gtt tac agt ggg aga gag ttg aac cac cct 3195 Gly Thr His Arg Lys Ile Val Tyr Ser Gly Arg Glu Leu Asn His Pro 765 770 775 ttc gga ctg tcg cat cat gga aat tat gtg ttc tgg act gat tat atg 3243 Phe Gly Leu Ser His His Gly Asn Tyr Val Phe Trp Thr Asp Tyr Met 780 785 790 aat ggt tcc att ttt caa cta gat ttg ata aca agt gag gtg aca ttg 3291 Asn Gly Ser Ile Phe Gln Leu Asp Leu Ile Thr Ser Glu Val Thr Leu 795 800 805 810 ctg agg cat gaa aga cca ccc cta ttt ggg ctt cag att tat gat cca 3339 Leu Arg His Glu Arg Pro Pro Leu Phe Gly Leu Gln Ile Tyr Asp Pro 815 820 825 cga aag caa caa ggt gac aat atg tgc cga gta aat aat ggg ggc tgt 3387 Arg Lys Gln Gln Gly Asp Asn Met Cys Arg Val Asn Asn Gly Gly Cys 830 835 840 agt aca ctt tgc ttg gct atc cca gga ggc cgg gtg tgt gct tgt gcc 3435 Ser Thr Leu Cys Leu Ala Ile Pro Gly Gly Arg Val Cys Ala Cys Ala 845 850 855 gat aat caa ctt ttg gat gaa aat ggg aca act tgc aca ttt aat cct 3483 Asp Asn Gln Leu Leu Asp Glu Asn Gly Thr Thr Cys Thr Phe Asn Pro 860 865 870 gga gaa gca cta cct cac ata tgt aaa gct gga gag ttt cgc tgc aaa 3531 Gly Glu Ala Leu Pro His Ile Cys Lys Ala Gly Glu Phe Arg Cys Lys 875 880 885 890 aac aga cac tgt atc caa gct cgg tgg aaa tgt gat ggc gac gat gac 3579 Asn Arg His Cys Ile Gln Ala Arg Trp Lys Cys Asp Gly Asp Asp Asp 895 900 905 tgc cta gac gga agc gat gag gat tca gta aac tgc ttc aat cat agc 3627 Cys Leu Asp Gly Ser Asp Glu Asp Ser Val Asn Cys Phe Asn His Ser 910 915 920 tgt cct gat gat cag ttt aaa tgc cag aat aat cgc tgc atc ccc aag 3675 Cys Pro Asp Asp Gln Phe Lys Cys Gln Asn Asn Arg Cys Ile Pro Lys 925 930 935 aga tgg ctt tgt gat gga gct aat gac tgt ggg agc aat gaa gat gaa 3723 Arg Trp Leu Cys Asp Gly Ala Asn Asp Cys Gly Ser Asn Glu Asp Glu 940 945 950 tcc aat caa act tgc aca gcc aga aca tgc cag gta gac cag ttt tct 3771 Ser Asn Gln Thr Cys Thr Ala Arg Thr Cys Gln Val Asp Gln Phe Ser 955 960 965 970 tgc gga aat ggg cgt tgc att ccc aga gca tgg ctg tgt gac agg gaa 3819 Cys Gly Asn Gly Arg Cys Ile Pro Arg Ala Trp Leu Cys Asp Arg Glu 975 980 985 gac gac tgt ggt gac cag aca gat gaa atg gca tct tgt gaa ttc cca 3867 Asp Asp Cys Gly Asp Gln Thr Asp Glu Met Ala Ser Cys Glu Phe Pro 990 995 1000 act tgt gag cca cta acc caa ttc gta tgc aaa agt gga aga tgc 3912 Thr Cys Glu Pro Leu Thr Gln Phe Val Cys Lys Ser Gly Arg Cys 1005 1010 1015 att agc agc aaa tgg cac tgc gac tct gat gac gac tgt ggg gac 3957 Ile Ser Ser Lys Trp His Cys Asp Ser Asp Asp Asp Cys Gly Asp 1020 1025 1030 ggg agt gat gag gtg ggc tgt gtt cac tct tgc ttt gat aat cag 4002 Gly Ser Asp Glu Val Gly Cys Val His Ser Cys Phe Asp Asn Gln 1035 1040 1045 ttc aga tgt tcc agt ggc aga tgc atc cca ggc cac tgg gcc tgt 4047 Phe Arg Cys Ser Ser Gly Arg Cys Ile Pro Gly His Trp Ala Cys 1050 1055 1060 gat ggt gac aat gac tgt ggg gac ttc agt gat gaa gcc cag atc 4092 Asp Gly Asp Asn Asp Cys Gly Asp Phe Ser Asp Glu Ala Gln Ile 1065 1070 1075 aat tgt act aaa gaa gag att cat tct cct gct ggt tgt aac gga 4137 Asn Cys Thr Lys Glu Glu Ile His Ser Pro Ala Gly Cys Asn Gly 1080 1085 1090 aat gaa ttt cag tgc cac cct gat ggt aat tgc gtt cct gat ttg 4182 Asn Glu Phe Gln Cys His Pro Asp Gly Asn Cys Val Pro Asp Leu 1095 1100 1105 tgg cgc tgt gat gga gaa aaa gac tgt gaa gat ggt agt gat gaa 4227 Trp Arg Cys Asp Gly Glu Lys Asp Cys Glu Asp Gly Ser Asp Glu 1110 1115 1120 aaa ggt tgc aat ggt acc ata cga ttg tgt gac cac aaa acc aag 4272 Lys Gly Cys Asn Gly Thr Ile Arg Leu Cys Asp His Lys Thr Lys 1125 1130 1135 ttt tcc tgt tgg agt aca ggg aga tgc atc aac aaa gca tgg gtg 4317 Phe Ser Cys Trp Ser Thr Gly Arg Cys Ile Asn Lys Ala Trp Val 1140 1145 1150 tgt gat gga gat att gat tgc gaa gat cag tca gat gaa gat gac 4362 Cys Asp Gly Asp Ile Asp Cys Glu Asp Gln Ser Asp Glu Asp Asp 1155 1160 1165 tgt gac agt ttc ttg tgt gga cca ccc aag cat cct tgt gct aat 4407 Cys Asp Ser Phe Leu Cys Gly Pro Pro Lys His Pro Cys Ala Asn 1170 1175 1180 gac acc tca gtc tgc ctg cag cca gag aaa ctc tgc aat ggg aaa 4452 Asp Thr Ser Val Cys Leu Gln Pro Glu Lys Leu Cys Asn Gly Lys 1185 1190 1195 aag gat tgt cct gat ggc tct gat gaa ggc tat ctc tgt gat gag 4497 Lys Asp Cys Pro Asp Gly Ser Asp Glu Gly Tyr Leu Cys Asp Glu 1200 1205 1210 tgt tcg ctg aac aat gga ggc tgt agc aac cac tgt tct gtt gtt 4542 Cys Ser Leu Asn Asn Gly Gly Cys Ser Asn His Cys Ser Val Val 1215 1220 1225 cct gga aga gga att gtc tgt tcc tgc cct gaa gga ctt caa ctc 4587 Pro Gly Arg Gly Ile Val Cys Ser Cys Pro Glu Gly Leu Gln Leu 1230 1235 1240 aac aaa gac aat aaa aca tgt gaa att gtg gat tat tgt agc aat 4632 Asn Lys Asp Asn Lys Thr Cys Glu Ile Val Asp Tyr Cys Ser Asn 1245 1250 1255 cat cta aag tgc agc caa gta tgt gag cag cac aag cac aca gtc 4677 His Leu Lys Cys Ser Gln Val Cys Glu Gln His Lys His Thr Val 1260 1265 1270 aag tgc tca tgt tat gaa ggt tgg aag ctg gat gta gac ggt gaa 4722 Lys Cys Ser Cys Tyr Glu Gly Trp Lys Leu Asp Val Asp Gly Glu 1275 1280 1285 agt tgt aca agt gtt gat cct ttt gaa gca ttc atc atc ttt tct 4767 Ser Cys Thr Ser Val Asp Pro Phe Glu Ala Phe Ile Ile Phe Ser 1290 1295 1300 att cgt cat gag atc aga agg att gat ctt cac aaa aga gac tat 4812 Ile Arg His Glu Ile Arg Arg Ile Asp Leu His Lys Arg Asp Tyr 1305 1310 1315 agt cta ctt gtt cct gga ttg aga aac aca ata gca ctt gat ttt 4857 Ser Leu Leu Val Pro Gly Leu Arg Asn Thr Ile Ala Leu Asp Phe 1320 1325 1330 cac ttc aat caa agt tta ctt tat tgg aca gat gtt gta gaa gac 4902 His Phe Asn Gln Ser Leu Leu Tyr Trp Thr Asp Val Val Glu Asp 1335 1340 1345 aga ata tac cgg gga aag ctt tct gaa agt gga ggt gtc agt gcc 4947 Arg Ile Tyr Arg Gly Lys Leu Ser Glu Ser Gly Gly Val Ser Ala 1350 1355 1360 att gaa gtg gtt gtg gag cat ggc ctg gct act cca gaa ggc ctg 4992 Ile Glu Val Val Val Glu His Gly Leu Ala Thr Pro Glu Gly Leu 1365 1370 1375 aca gtc gac tgg ata gca gga aac ata tac tgg ata gac agc aat 5037 Thr Val Asp Trp Ile Ala Gly Asn Ile Tyr Trp Ile Asp Ser Asn 1380 1385 1390 ctg gac caa atc gaa gtg gcc aaa cta gat ggc tcc cta aga act 5082 Leu Asp Gln Ile Glu Val Ala Lys Leu Asp Gly Ser Leu Arg Thr 1395 1400 1405 aca cta ata gca gga gcc atg gaa cac ccc agg gcc att gct ttg 5127 Thr Leu Ile Ala Gly Ala Met Glu His Pro Arg Ala Ile Ala Leu 1410 1415 1420 gac cca aga tat gga att ctt ttc tgg aca gac tgg gat gca aat 5172 Asp Pro Arg Tyr Gly Ile Leu Phe Trp Thr Asp Trp Asp Ala Asn 1425 1430 1435 ttt cct cgc att gaa tct gcc tct atg agt ggt gct ggg aga aaa 5217 Phe Pro Arg Ile Glu Ser Ala Ser Met Ser Gly Ala Gly Arg Lys 1440 1445 1450 acc atc tat aaa gac atg aaa act ggg gct tgg cct aat gga cta 5262 Thr Ile Tyr Lys Asp Met Lys Thr Gly Ala Trp Pro Asn Gly Leu 1455 1460 1465 act gtg gac cac ttt gag aaa agg ata gtg tgg aca gac gcc agg 5307 Thr Val Asp His Phe Glu Lys Arg Ile Val Trp Thr Asp Ala Arg 1470 1475 1480 tca gat gct att tat tca gcc ctc tat gat gga aca aac atg ata 5352 Ser Asp Ala Ile Tyr Ser Ala Leu Tyr Asp Gly Thr Asn Met Ile 1485 1490 1495 gaa atc atc cga ggt cat gaa tac ctt tcc cat ccc ttt gct gtg 5397 Glu Ile Ile Arg Gly His Glu Tyr Leu Ser His Pro Phe Ala Val 1500 1505 1510 tct cta tat ggg agt gaa gtc tac tgg aca gac tgg agg acc aac 5442 Ser Leu Tyr Gly Ser Glu Val Tyr Trp Thr Asp Trp Arg Thr Asn 1515 1520 1525 aca ttg tcc aaa gcc aat aag tgg aca ggg cag aat gtc agt gtg 5487 Thr Leu Ser Lys Ala Asn Lys Trp Thr Gly Gln Asn Val Ser Val 1530 1535 1540 att cag aaa acc agt gca cag cca ttt gac ctt cag ata tac cat 5532 Ile Gln Lys Thr Ser Ala Gln Pro Phe Asp Leu Gln Ile Tyr His 1545 1550 1555 ccc agt cgc cag cca cag gct ccc aat cct tgt gca gct aat gat 5577 Pro Ser Arg Gln Pro Gln Ala Pro Asn Pro Cys Ala Ala Asn Asp 1560 1565 1570 ggc aaa ggc ccc tgc tct cac atg tgt cta atc aat cac aat agg 5622 Gly Lys Gly Pro Cys Ser His Met Cys Leu Ile Asn His Asn Arg 1575 1580 1585 agt gct gcc tgt gcg tgc ccc cac ttg atg aag ctt tct tca gac 5667 Ser Ala Ala Cys Ala Cys Pro His Leu Met Lys Leu Ser Ser Asp 1590 1595 1600 aag aag acc tgc tat gaa atg aaa aaa ttt ctt ctt tat gca aga 5712 Lys Lys Thr Cys Tyr Glu Met Lys Lys Phe Leu Leu Tyr Ala Arg 1605 1610 1615 cgt tct gaa atc aga gga gtg gat att gac aat cca tac ttt aac 5757 Arg Ser Glu Ile Arg Gly Val Asp Ile Asp Asn Pro Tyr Phe Asn 1620 1625 1630 ttc atc acg gca ttt aca gtc cct gat att gat gac gtt act gtg 5802 Phe Ile Thr Ala Phe Thr Val Pro Asp Ile Asp Asp Val Thr Val 1635 1640 1645 ata gac ttc gat gca tct gag gaa cgt tta tac tgg aca gat att 5847 Ile Asp Phe Asp Ala Ser Glu Glu Arg Leu Tyr Trp Thr Asp Ile 1650 1655 1660 aaa aca caa acc att aaa cga gct ttt att aac gga act ggg tta 5892 Lys Thr Gln Thr Ile Lys Arg Ala Phe Ile Asn Gly Thr Gly Leu 1665 1670 1675 gaa act gtt att tca aga gat att cag agt atc aga ggg cta gca 5937 Glu Thr Val Ile Ser Arg Asp Ile Gln Ser Ile Arg Gly Leu Ala 1680 1685 1690 gtg gat tgg gtg tca cgt aat tta tac tgg att agc tca gaa ttt 5982 Val Asp Trp Val Ser Arg Asn Leu Tyr Trp Ile Ser Ser Glu Phe 1695 1700 1705 gat gaa acg caa att aat gtg gca agg cta gat ggc tct ttg aaa 6027 Asp Glu Thr Gln Ile Asn Val Ala Arg Leu Asp Gly Ser Leu Lys 1710 1715 1720 acc tca att atc cat gga atc gat aag cca cag tgt ctt gca gct 6072 Thr Ser Ile Ile His Gly Ile Asp Lys Pro Gln Cys Leu Ala Ala 1725 1730 1735 cac cca gtc agg gga aaa ctc tac tgg acc gat gga aac aca att 6117 His Pro Val Arg Gly Lys Leu Tyr Trp Thr Asp Gly Asn Thr Ile 1740 1745 1750 aac atg gca aat atg gat ggc agt aat agc aag att ctg ttt cag 6162 Asn Met Ala Asn Met Asp Gly Ser Asn Ser Lys Ile Leu Phe Gln 1755 1760 1765 aat cag aag gag cca gtt ggt cta tcg ata gac tat gtg gaa aac 6207 Asn Gln Lys Glu Pro Val Gly Leu Ser Ile Asp Tyr Val Glu Asn 1770 1775 1780 aag ctt tat tgg atc agt tcg ggg aat gga acc ata aat aga tgc 6252 Lys Leu Tyr Trp Ile Ser Ser Gly Asn Gly Thr Ile Asn Arg Cys 1785 1790 1795 aac ctg gat ggt ggt aat tta gaa gta atc gag tca atg aaa gaa 6297 Asn Leu Asp Gly Gly Asn Leu Glu Val Ile Glu Ser Met Lys Glu 1800 1805 1810 gaa tta aca aaa gct aca gcc cta acc atc atg gat aag aaa ctg 6342 Glu Leu Thr Lys Ala Thr Ala Leu Thr Ile Met Asp Lys Lys Leu 1815 1820 1825 tgg tgg gca gac caa aac tta gcc cag cta gga acc tgc agc aaa 6387 Trp Trp Ala Asp Gln Asn Leu Ala Gln Leu Gly Thr Cys Ser Lys 1830 1835 1840 aga gac gga aga aac ccc acc atc cta cgg aat aag act tct ggg 6432 Arg Asp Gly Arg Asn Pro Thr Ile Leu Arg Asn Lys Thr Ser Gly 1845 1850 1855 gta gtt cat atg aaa gtc tat gat aaa gaa gca cag caa ggc agc 6477 Val Val His Met Lys Val Tyr Asp Lys Glu Ala Gln Gln Gly Ser 1860 1865 1870 aat tcc tgc caa cta aac aat ggt gga tgc tct caa ctt tgt tta 6522 Asn Ser Cys Gln Leu Asn Asn Gly Gly Cys Ser Gln Leu Cys Leu 1875 1880 1885 cca aca tct gaa act aca agg act tgt atg tgt aca gtg gga tat 6567 Pro Thr Ser Glu Thr Thr Arg Thr Cys Met Cys Thr Val Gly Tyr 1890 1895 1900 tat ctc caa aag aac cgt atg tca tgt caa ggt ata gaa tca ttt 6612 Tyr Leu Gln Lys Asn Arg Met Ser Cys Gln Gly Ile Glu Ser Phe 1905 1910 1915 ctt atg tac tct gtt cat gaa gga atc agg gga ata cct ctt gaa 6657 Leu Met Tyr Ser Val His Glu Gly Ile Arg Gly Ile Pro Leu Glu 1920 1925 1930 cca agt gac aaa atg gat gct ttg atg cct ata tca gga act tca 6702 Pro Ser Asp Lys Met Asp Ala Leu Met Pro Ile Ser Gly Thr Ser 1935 1940 1945 ttt gcc gtg gga ata gat ttc cat gca gaa aat gat acc atc tac 6747 Phe Ala Val Gly Ile Asp Phe His Ala Glu Asn Asp Thr Ile Tyr 1950 1955 1960 tgg aca gac atg ggc ttc aat aaa att agc aga gct aaa aga gat 6792 Trp Thr Asp Met Gly Phe Asn Lys Ile Ser Arg Ala Lys Arg Asp 1965 1970 1975 cag act tgg aaa gaa gat atc att acc aat ggc ttg gga aga gtg 6837 Gln Thr Trp Lys Glu Asp Ile Ile Thr Asn Gly Leu Gly Arg Val 1980 1985 1990 gaa ggg ata gct gtt gac tgg att gct ggt aac ata tat tgg aca 6882 Glu Gly Ile Ala Val Asp Trp Ile Ala Gly Asn Ile Tyr Trp Thr 1995 2000 2005 gat cat ggt ttc aac tta att gaa gtt gca aga ctc aat ggt tct 6927 Asp His Gly Phe Asn Leu Ile Glu Val Ala Arg Leu Asn Gly Ser 2010 2015 2020 ttc cgt tat gta att att tcc caa ggc ctg gat caa cca aga tct 6972 Phe Arg Tyr Val Ile Ile Ser Gln Gly Leu Asp Gln Pro Arg Ser 2025 2030 2035 ata gct gtg cac cca gag aaa ggc ctc ttg ttc tgg act gaa tgg 7017 Ile Ala Val His Pro Glu Lys Gly Leu Leu Phe Trp Thr Glu Trp 2040 2045 2050 gga caa atg ccc tgt att gga aag gct cgc ttg gat ggc tca gag 7062 Gly Gln Met Pro Cys Ile Gly Lys Ala Arg Leu Asp Gly Ser Glu 2055 2060 2065 aag gtt gtc ctt gta agc atg gga ata gca tgg ccg aat ggc atc 7107 Lys Val Val Leu Val Ser Met Gly Ile Ala Trp Pro Asn Gly Ile 2070 2075 2080 tcc atc gac tat gag gaa aat aaa ttg tac tgg tgt gat gct cgc 7152 Ser Ile Asp Tyr Glu Glu Asn Lys Leu Tyr Trp Cys Asp Ala Arg 2085 2090 2095 aca gac aag ata gag aga atc gac ctt gag act gga ggg aat cgc 7197 Thr Asp Lys Ile Glu Arg Ile Asp Leu Glu Thr Gly Gly Asn Arg 2100 2105 2110 gag atg gtg ctg tca gga agc aat gtg gat atg ttt tca gtt gca 7242 Glu Met Val Leu Ser Gly Ser Asn Val Asp Met Phe Ser Val Ala 2115 2120 2125 gtc ttt ggg gct tac atc tac tgg tct gac aga gca cat gca aac 7287 Val Phe Gly Ala Tyr Ile Tyr Trp Ser Asp Arg Ala His Ala Asn 2130 2135 2140 ggg tct gtc aga agg ggc cac aag aat gat gcc aca gaa acg ata 7332 Gly Ser Val Arg Arg Gly His Lys Asn Asp Ala Thr Glu Thr Ile 2145 2150 2155 acc atg aga acc ggc ctt gga gtc aac ctg aag gag gtt aaa ata 7377 Thr Met Arg Thr Gly Leu Gly Val Asn Leu Lys Glu Val Lys Ile 2160 2165 2170 ttt aac cga gta aga gag aaa ggg acc aat gtt tgt gcc agg gac 7422 Phe Asn Arg Val Arg Glu Lys Gly Thr Asn Val Cys Ala Arg Asp 2175 2180 2185 aat ggt ggc tgt aag caa ctc tgt ctt tat cga gga aat tcc cgg 7467 Asn Gly Gly Cys Lys Gln Leu Cys Leu Tyr Arg Gly Asn Ser Arg 2190 2195 2200 aga act tgt gct tgt gcc cat gga tat ttg gca gaa gat gga gtt 7512 Arg Thr Cys Ala Cys Ala His Gly Tyr Leu Ala Glu Asp Gly Val 2205 2210 2215 act tgc ctg agg cat gaa ggc tat tta ctg tat tca gga aga aca 7557 Thr Cys Leu Arg His Glu Gly Tyr Leu Leu Tyr Ser Gly Arg Thr 2220 2225 2230 ata tta aaa agt ata cat ctt tct gat gaa acc aat tta aat tcc 7602 Ile Leu Lys Ser Ile His Leu Ser Asp Glu Thr Asn Leu Asn Ser 2235 2240 2245 cca ata agg cca tat gag aat cca cgt tat ttc aag aat gtc ata 7647 Pro Ile Arg Pro Tyr Glu Asn Pro Arg Tyr Phe Lys Asn Val Ile 2250 2255 2260 gcc ttg gct ttt gac tat aat caa aga aga aaa ggt acc aac cga 7692 Ala Leu Ala Phe Asp Tyr Asn Gln Arg Arg Lys Gly Thr Asn Arg 2265 2270 2275 atc ttt tac agt gat gca cac ttt gga aat ata cag ctt att aaa 7737 Ile Phe Tyr Ser Asp Ala His Phe Gly Asn Ile Gln Leu Ile Lys 2280 2285 2290 gac aac tgg gaa gac aga caa gta att gtt gaa aat gtg ggt tct 7782 Asp Asn Trp Glu Asp Arg Gln Val Ile Val Glu Asn Val Gly Ser 2295 2300 2305 gtg gaa gga ctt gcc tat cac aga gcc tgg gat aca ctg tac tgg 7827 Val Glu Gly Leu Ala Tyr His Arg Ala Trp Asp Thr Leu Tyr Trp 2310 2315 2320 aca agc tct acc acc tca tcc atc acc aga cac act gtg gac cag 7872 Thr Ser Ser Thr Thr Ser Ser Ile Thr Arg His Thr Val Asp Gln 2325 2330 2335 act cgg cct gga gca ttt gac agg gaa gct gtc atc acc atg tca 7917 Thr Arg Pro Gly Ala Phe Asp Arg Glu Ala Val Ile Thr Met Ser 2340 2345 2350 gaa gat gac cat cca cat gtg cta gcc ttg gat gaa tgt caa aat 7962 Glu Asp Asp His Pro His Val Leu Ala Leu Asp Glu Cys Gln Asn 2355 2360 2365 tta atg ttt tgg acc aac tgg aat gaa caa cat cca agt atc atg 8007 Leu Met Phe Trp Thr Asn Trp Asn Glu Gln His Pro Ser Ile Met 2370 2375 2380 aga tct act ctg act ggg aaa aat gct caa gtg gtg gtc agt aca 8052 Arg Ser Thr Leu Thr Gly Lys Asn Ala Gln Val Val Val Ser Thr 2385 2390 2395 gac ata ctc act cca aat gga ctt act atc gac tac cgt gca gag 8097 Asp Ile Leu Thr Pro Asn Gly Leu Thr Ile Asp Tyr Arg Ala Glu 2400 2405 2410 aag ctg tat ttc tca gat ggc agt cta gga aaa att gaa agg tgt 8142 Lys Leu Tyr Phe Ser Asp Gly Ser Leu Gly Lys Ile Glu Arg Cys 2415 2420 2425 gaa tac gat gga tcc cag aga cat gtg ata gtt aaa tct ggg cca 8187 Glu Tyr Asp Gly Ser Gln Arg His Val Ile Val Lys Ser Gly Pro 2430 2435 2440 ggg act ttc ctc agt ttg gct gtt tat gac aat tat ata ttc tgg 8232 Gly Thr Phe Leu Ser Leu Ala Val Tyr Asp Asn Tyr Ile Phe Trp 2445 2450 2455 tcg gac tgg gga aga aga gct ata ctg cgg tcc aac aag tac aca 8277 Ser Asp Trp Gly Arg Arg Ala Ile Leu Arg Ser Asn Lys Tyr Thr 2460 2465 2470 gga gga gat aca aaa att ctt cgt tcc gat att cca cat cag cca 8322 Gly Gly Asp Thr Lys Ile Leu Arg Ser Asp Ile Pro His Gln Pro 2475 2480 2485 atg gga atc ata gct gtt gcc aat gac acc aat agc tgt gaa ctt 8367 Met Gly Ile Ile Ala Val Ala Asn Asp Thr Asn Ser Cys Glu Leu 2490 2495 2500 tct cca tgt gca tta ttg aat gga ggc tgc cat gac ttg tgc ctt 8412 Ser Pro Cys Ala Leu Leu Asn Gly Gly Cys His Asp Leu Cys Leu 2505 2510 2515 tta act ccc aat ggg aga gtg aat tgt tcc tgc aga ggg gac cga 8457 Leu Thr Pro Asn Gly Arg Val Asn Cys Ser Cys Arg Gly Asp Arg 2520 2525 2530 ata ttg cta gag gac aac aga tgt gtg act aaa aat tcc tcc tgc 8502 Ile Leu Leu Glu Asp Asn Arg Cys Val Thr Lys Asn Ser Ser Cys 2535 2540 2545 aac gct tat tcg gag ttt gaa tgt gga aat ggt gag tgc att gac 8547 Asn Ala Tyr Ser Glu Phe Glu Cys Gly Asn Gly Glu Cys Ile Asp 2550 2555 2560 tac cag ctc acc tgt gat ggc att cct cac tgt aaa gat aaa tca 8592 Tyr Gln Leu Thr Cys Asp Gly Ile Pro His Cys Lys Asp Lys Ser 2565 2570 2575 gat gaa aaa ctg ctc tac tgt gaa aac aga agc tgt cga aga ggc 8637 Asp Glu Lys Leu Leu Tyr Cys Glu Asn Arg Ser Cys Arg Arg Gly 2580 2585 2590 ttc aag cca tgc tat aat cgc cgc tgc att cct cat ggc aag tta 8682 Phe Lys Pro Cys Tyr Asn Arg Arg Cys Ile Pro His Gly Lys Leu 2595 2600 2605 tgt gat gga gaa aat gac tgc gga gac aac tct gat gaa tta gat 8727 Cys Asp Gly Glu Asn Asp Cys Gly Asp Asn Ser Asp Glu Leu Asp 2610 2615 2620 tgt aaa gtt tca acc tgt gcc acg gtt gag ttc cgc tgt gca gat 8772 Cys Lys Val Ser Thr Cys Ala Thr Val Glu Phe Arg Cys Ala Asp 2625 2630 2635 ggg act tgt att cca aga tca gca cga tgc aac cag aac ata gat 8817 Gly Thr Cys Ile Pro Arg Ser Ala Arg Cys Asn Gln Asn Ile Asp 2640 2645 2650 tgt gca gat gct tca gat gaa aag aac tgc aat aac aca gac tgc 8862 Cys Ala Asp Ala Ser Asp Glu Lys Asn Cys Asn Asn Thr Asp Cys 2655 2660 2665 aca cat ttc tat aag ctt gga gtg aaa acc aca ggg ttc ata aga 8907 Thr His Phe Tyr Lys Leu Gly Val Lys Thr Thr Gly Phe Ile Arg 2670 2675 2680 tgt aat tct acc tca ctg tgt gtt ctg cca acc tgg ata tgc gac 8952 Cys Asn Ser Thr Ser Leu Cys Val Leu Pro Thr Trp Ile Cys Asp 2685 2690 2695 ggg tct aat gac tgt gga gac tat tca gat gaa tta aag tgc cca 8997 Gly Ser Asn Asp Cys Gly Asp Tyr Ser Asp Glu Leu Lys Cys Pro 2700 2705 2710 gtt cag aac aaa cac aaa tgt gaa gaa aat tat ttt agt tgt cct 9042 Val Gln Asn Lys His Lys Cys Glu Glu Asn Tyr Phe Ser Cys Pro 2715 2720 2725 agt gga aga tgc att ttg aat acc tgg ata tgc gat ggt cag aaa 9087 Ser Gly Arg Cys Ile Leu Asn Thr Trp Ile Cys Asp Gly Gln Lys 2730 2735 2740 gat tgt gag gat gga cgt gat gaa ttc cac tgt gat tct tct tgc 9132 Asp Cys Glu Asp Gly Arg Asp Glu Phe His Cys Asp Ser Ser Cys 2745 2750 2755 tct tgg aac caa ttt gct tgt tcc gca caa aaa tgt att tct aag 9177 Ser Trp Asn Gln Phe Ala Cys Ser Ala Gln Lys Cys Ile Ser Lys 2760 2765 2770 cat tgg att tgt gat gga gaa gat gac tgt ggg gat ggg tta gat 9222 His Trp Ile Cys Asp Gly Glu Asp Asp Cys Gly Asp Gly Leu Asp 2775 2780 2785 gaa agt gac agc att tgt ggt gcc ata acc tgt gct gct gac atg 9267 Glu Ser Asp Ser Ile Cys Gly Ala Ile Thr Cys Ala Ala Asp Met 2790 2795 2800 ttc agc tgc cag ggc tct cgt gcc tgc gtg ccc cga cat tgg ctt 9312 Phe Ser Cys Gln Gly Ser Arg Ala Cys Val Pro Arg His Trp Leu 2805 2810 2815 tgt gat ggt gaa agg gac tgt cca gat gga agc gat gag ctt tcc 9357 Cys Asp Gly Glu Arg Asp Cys Pro Asp Gly Ser Asp Glu Leu Ser 2820 2825 2830 aca gca ggc tgc gct ccc aat aat aca tgt gat gaa aat gct ttc 9402 Thr Ala Gly Cys Ala Pro Asn Asn Thr Cys Asp Glu Asn Ala Phe 2835 2840 2845 atg tgc cat aat aaa gta tgc att ccc aag caa ttt gtt tgt gac 9447 Met Cys His Asn Lys Val Cys Ile Pro Lys Gln Phe Val Cys Asp 2850 2855 2860 cat gat gac gac tgt gga gat ggc tct gat gag tca ccg cag tgt 9492 His Asp Asp Asp Cys Gly Asp Gly Ser Asp Glu Ser Pro Gln Cys 2865 2870 2875 gga tac cga cag tgt ggt aca gaa gaa ttt agt tgt gct gat ggg 9537 Gly Tyr Arg Gln Cys Gly Thr Glu Glu Phe Ser Cys Ala Asp Gly 2880 2885 2890 cgg tgt ctt cta aat act caa tgg cag tgt gat gga gac ttt gac 9582 Arg Cys Leu Leu Asn Thr Gln Trp Gln Cys Asp Gly Asp Phe Asp 2895 2900 2905 tgt cct gac cat tct gat gaa gca cct tta aac cca aag tgt aaa 9627 Cys Pro Asp His Ser Asp Glu Ala Pro Leu Asn Pro Lys Cys Lys 2910 2915 2920 agt gca gaa cag tca tgc aac agt tca ttt ttt atg tgc aaa aat 9672 Ser Ala Glu Gln Ser Cys Asn Ser Ser Phe Phe Met Cys Lys Asn 2925 2930 2935 ggc agg tgc att ccc agt gga ggt ctt tgt gac aat aag gat gac 9717 Gly Arg Cys Ile Pro Ser Gly Gly Leu Cys Asp Asn Lys Asp Asp 2940 2945 2950 tgt ggc gat ggt tca gat gag aga aac tgc cat ata aat gaa tgt 9762 Cys Gly Asp Gly Ser Asp Glu Arg Asn Cys His Ile Asn Glu Cys 2955 2960 2965 ttg agt aag aaa gtc agt gga tgt tct caa gat tgt caa gac ctt 9807 Leu Ser Lys Lys Val Ser Gly Cys Ser Gln Asp Cys Gln Asp Leu 2970 2975 2980 ccg gtc agt tat aag tgc aaa tgc tgg cct gga ttc caa ctg aag 9852 Pro Val Ser Tyr Lys Cys Lys Cys Trp Pro Gly Phe Gln Leu Lys 2985 2990 2995 gat gac ggc aaa aca tgt gta gac att gat gaa tgc tct tca ggc 9897 Asp Asp Gly Lys Thr Cys Val Asp Ile Asp Glu Cys Ser Ser Gly 3000 3005 3010 ttt ccc tgt agc cag caa tgc atc aat aca tac ggg act tac aag 9942 Phe Pro Cys Ser Gln Gln Cys Ile Asn Thr Tyr Gly Thr Tyr Lys 3015 3020 3025 tgc ctc tgt aca gat ggg tat gaa ata caa cct gat aac cca aat 9987 Cys Leu Cys Thr Asp Gly Tyr Glu Ile Gln Pro Asp Asn Pro Asn 3030 3035 3040 ggc tgc aaa tcg ctc tca gat gaa gaa cct ttt tta att ctt gct 10032 Gly Cys Lys Ser Leu Ser Asp Glu Glu Pro Phe Leu Ile Leu Ala 3045 3050 3055 gat cat cat gag ata agg aaa att agc act gat ggc tcc aac tac 10077 Asp His His Glu Ile Arg Lys Ile Ser Thr Asp Gly Ser Asn Tyr 3060 3065 3070 aca ctt tta aaa cag gga tta aac aat gtt att gct ata gac ttt 10122 Thr Leu Leu Lys Gln Gly Leu Asn Asn Val Ile Ala Ile Asp Phe 3075 3080 3085 gat tac aga gaa gaa ttc atc tat tgg atc gat tct agc cga ccc 10167 Asp Tyr Arg Glu Glu Phe Ile Tyr Trp Ile Asp Ser Ser Arg Pro 3090 3095 3100 aat ggc agt cgc ata aat aga atg tgt tta aat gga agt gac att 10212 Asn Gly Ser Arg Ile Asn Arg Met Cys Leu Asn Gly Ser Asp Ile 3105 3110 3115 aag gta gtt cat aac aca gcg gtc ccc aat gca ctt gct gtc gat 10257 Lys Val Val His Asn Thr Ala Val Pro Asn Ala Leu Ala Val Asp 3120 3125 3130 tgg att gga aaa aac ctc tat tgg tct gac aca gaa aaa aga atc 10302 Trp Ile Gly Lys Asn Leu Tyr Trp Ser Asp Thr Glu Lys Arg Ile 3135 3140 3145 att gaa gta tcc aaa ctc aat ggc ttg tac cct act ata ctc gtt 10347 Ile Glu Val Ser Lys Leu Asn Gly Leu Tyr Pro Thr Ile Leu Val 3150 3155 3160 agc aaa agg ctg aag ttt ccc aga gac ttg tct tta gat cct caa 10392 Ser Lys Arg Leu Lys Phe Pro Arg Asp Leu Ser Leu Asp Pro Gln 3165 3170 3175 gct gga tat ttg tat tgg att gac tgc tgc gag tat cct cat att 10437 Ala Gly Tyr Leu Tyr Trp Ile Asp Cys Cys Glu Tyr Pro His Ile 3180 3185 3190 ggc cgt gtt gga atg gat gga acc aat cag agt gtt gtc ata gaa 10482 Gly Arg Val Gly Met Asp Gly Thr Asn Gln Ser Val Val Ile Glu 3195 3200 3205 acc aag att tct aga cct atg gca cta aca ata gat tat gtt aat 10527 Thr Lys Ile Ser Arg Pro Met Ala Leu Thr Ile Asp Tyr Val Asn 3210 3215 3220 cgt aga ctc tac tgg gcc gat gaa aat cac att gaa ttt agc aac 10572 Arg Arg Leu Tyr Trp Ala Asp Glu Asn His Ile Glu Phe Ser Asn 3225 3230 3235 atg gat gga tct cat aga cac aaa gtc cct aat caa gat att cca 10617 Met Asp Gly Ser His Arg His Lys Val Pro Asn Gln Asp Ile Pro 3240 3245 3250 ggg gtg att gca cta aca ttg ttt gaa gac tac atc tac tgg act 10662 Gly Val Ile Ala Leu Thr Leu Phe Glu Asp Tyr Ile Tyr Trp Thr 3255 3260 3265 gat ggg aaa acc aag tca ctc agc cgt gcc cat aaa aca tcg gga 10707 Asp Gly Lys Thr Lys Ser Leu Ser Arg Ala His Lys Thr Ser Gly 3270 3275 3280 gca gac aga ctc tca ctg att tac tca tgg cat gcc atc aca gat 10752 Ala Asp Arg Leu Ser Leu Ile Tyr Ser Trp His Ala Ile Thr Asp 3285 3290 3295 atc cag gtg tat cat tct tat aga caa cct gat gtc tcc aaa cat 10797 Ile Gln Val Tyr His Ser Tyr Arg Gln Pro Asp Val Ser Lys His 3300 3305 3310 ctc tgc atg ata aat aat ggt ggt tgc agt cat ttg tgc ctt tta 10842 Leu Cys Met Ile Asn Asn Gly Gly Cys Ser His Leu Cys Leu Leu 3315 3320 3325 gcc cct gga aaa acc cac act tgt gca tgt ccc act aac ttc tat 10887 Ala Pro Gly Lys Thr His Thr Cys Ala Cys Pro Thr Asn Phe Tyr 3330 3335 3340 ctg gca gct gat aat agg act tgc tta tcc aac tgc aca gcc agc 10932 Leu Ala Ala Asp Asn Arg Thr Cys Leu Ser Asn Cys Thr Ala Ser 3345 3350 3355 cag ttt cgt tgc aaa act gac aaa tgt att cca ttc tgg tgg aaa 10977 Gln Phe Arg Cys Lys Thr Asp Lys Cys Ile Pro Phe Trp Trp Lys 3360 3365 3370 tgt gac acc gtg gat gac tgt ggt gat gga tct gat gaa cct gat 11022 Cys Asp Thr Val Asp Asp Cys Gly Asp Gly Ser Asp Glu Pro Asp 3375 3380 3385 gac tgt cct gaa ttt aga tgt cag cca ggc cga ttt cag tgt ggg 11067 Asp Cys Pro Glu Phe Arg Cys Gln Pro Gly Arg Phe Gln Cys Gly 3390 3395 3400 act gga ctc tgt gct cta cca gct ttc atc tgt gat gga gag aat 11112 Thr Gly Leu Cys Ala Leu Pro Ala Phe Ile Cys Asp Gly Glu Asn 3405 3410 3415 gat tgt gga gac aat tct gat gaa ctc aac tgt gac aca cat gtc 11157 Asp Cys Gly Asp Asn Ser Asp Glu Leu Asn Cys Asp Thr His Val 3420 3425 3430 tgc ctg tca ggt caa ttc aaa tgt acc aag aac cag aaa tgt atc 11202 Cys Leu Ser Gly Gln Phe Lys Cys Thr Lys Asn Gln Lys Cys Ile 3435 3440 3445 cca gta aac tta aga tgt aat ggg caa gat gac tgt ggt gat gag 11247 Pro Val Asn Leu Arg Cys Asn Gly Gln Asp Asp Cys Gly Asp Glu 3450 3455 3460 gaa gat gaa aga gac tgt cct gaa aac agc tgt tct cca gac tat 11292 Glu Asp Glu Arg Asp Cys Pro Glu Asn Ser Cys Ser Pro Asp Tyr 3465 3470 3475 ttc cag tgt aag act acg aag cat tgc att tcc aag ctg tgg gtt 11337 Phe Gln Cys Lys Thr Thr Lys His Cys Ile Ser Lys Leu Trp Val 3480 3485 3490 tgt gac gag gat cca gac tgt gca gat gca tca gac gag gcc aac 11382 Cys Asp Glu Asp Pro Asp Cys Ala Asp Ala Ser Asp Glu Ala Asn 3495 3500 3505 tgc gat aaa aag act tgt gga cct cat gaa ttc cag tgt aaa aac 11427 Cys Asp Lys Lys Thr Cys Gly Pro His Glu Phe Gln Cys Lys Asn 3510 3515 3520 aac aac tgt att ccc gat cac tgg cgg tgt gat agc caa aat gac 11472 Asn Asn Cys Ile Pro Asp His Trp Arg Cys Asp Ser Gln Asn Asp 3525 3530 3535 tgc agt gat aat tca gat gaa gaa aac tgt aag cca cag aca tgt 11517 Cys Ser Asp Asn Ser Asp Glu Glu Asn Cys Lys Pro Gln Thr Cys 3540 3545 3550 aca ttg aaa gat ttc ctc tgt gcc aat ggg gac tgt gtt tct tca 11562 Thr Leu Lys Asp Phe Leu Cys Ala Asn Gly Asp Cys Val Ser Ser 3555 3560 3565 agg ttt tgg tgt gat gga gat ttt gac tgt gca gat ggc tct gat 11607 Arg Phe Trp Cys Asp Gly Asp Phe Asp Cys Ala Asp Gly Ser Asp 3570 3575 3580 gag aga aat tgt gag aca agt tgt tcc aaa gat cag ttc cgg tgt 11652 Glu Arg Asn Cys Glu Thr Ser Cys Ser Lys Asp Gln Phe Arg Cys 3585 3590 3595 tcc aat ggt cag tgt ata cca gca aaa tgg aaa tgt gat ggc cat 11697 Ser Asn Gly Gln Cys Ile Pro Ala Lys Trp Lys Cys Asp Gly His 3600 3605 3610 gaa gac tgc aaa tat ggg gaa gat gag aaa agc tgt gag cca gct 11742 Glu Asp Cys Lys Tyr Gly Glu Asp Glu Lys Ser Cys Glu Pro Ala 3615 3620 3625 tct cct act tgc tca tca cgt gaa tat ata tgt gcc agt gat gga 11787 Ser Pro Thr Cys Ser Ser Arg Glu Tyr Ile Cys Ala Ser Asp Gly 3630 3635 3640 tgt att tca gca tct ttg aaa tgt aat gga gaa tat gat tgt gct 11832 Cys Ile Ser Ala Ser Leu Lys Cys Asn Gly Glu Tyr Asp Cys Ala 3645 3650 3655 gat ggt tca gat gag atg gac tgt gtg act gaa tgt aag gaa gat 11877 Asp Gly Ser Asp Glu Met Asp Cys Val Thr Glu Cys Lys Glu Asp 3660 3665 3670 cag ttt cgg tgc aaa aat aaa gcc cac tgt att cca att aga tgg 11922 Gln Phe Arg Cys Lys Asn Lys Ala His Cys Ile Pro Ile Arg Trp 3675 3680 3685 ctg tgt gat gga att cat gac tgt gtg gat ggc agt gat gaa gag 11967 Leu Cys Asp Gly Ile His Asp Cys Val Asp Gly Ser Asp Glu Glu 3690 3695 3700 aac tgt gaa aga gga gga aat ata tgt aga gct gat gag ttc ctt 12012 Asn Cys Glu Arg Gly Gly Asn Ile Cys Arg Ala Asp Glu Phe Leu 3705 3710 3715 tgc aat aat tct ctc tgc aaa cta cat ttc tgg gtg tgt gat gga 12057 Cys Asn Asn Ser Leu Cys Lys Leu His Phe Trp Val Cys Asp Gly 3720 3725 3730 gag gac gac tgt gga gac aac tct gat gaa gcc cct gat atg tgt 12102 Glu Asp Asp Cys Gly Asp Asn Ser Asp Glu Ala Pro Asp Met Cys 3735 3740 3745 gtc aaa ttt ctt tgt cca tcc acg aga cct cac aga tgc aga aat 12147 Val Lys Phe Leu Cys Pro Ser Thr Arg Pro His Arg Cys Arg Asn 3750 3755 3760 aac aga ata tgc cta cag tcg gag caa atg tgc aat ggg att gat 12192 Asn Arg Ile Cys Leu Gln Ser Glu Gln Met Cys Asn Gly Ile Asp 3765 3770 3775 gaa tgc ggt gac aat tca gat gaa gat cac tgt ggt ggt aag ctg 12237 Glu Cys Gly Asp Asn Ser Asp Glu Asp His Cys Gly Gly Lys Leu 3780 3785 3790 aca tat aaa gca agg cct tgt aaa aag gat gag ttt gct tgt agt 12282 Thr Tyr Lys Ala Arg Pro Cys Lys Lys Asp Glu Phe Ala Cys Ser 3795 3800 3805 aat aaa aaa tgc atc cct atg gat ctc cag tgt gat cga ctt gat 12327 Asn Lys Lys Cys Ile Pro Met Asp Leu Gln Cys Asp Arg Leu Asp 3810 3815 3820 gac tgc gga gat ggt tca gat gag caa gga tgc aga ata gct cct 12372 Asp Cys Gly Asp Gly Ser Asp Glu Gln Gly Cys Arg Ile Ala Pro 3825 3830 3835 act gaa tat acc tgt gaa gat aat gtg aat cca tgt gga gat gat 12417 Thr Glu Tyr Thr Cys Glu Asp Asn Val Asn Pro Cys Gly Asp Asp 3840 3845 3850 gca tat tgt aat caa ata aaa aca tct gtt ttc tgt cgc tgt aag 12462 Ala Tyr Cys Asn Gln Ile Lys Thr Ser Val Phe Cys Arg Cys Lys 3855 3860 3865 cct gga ttt cag aga aac atg aaa aac aga caa tgt gaa gac ctt 12507 Pro Gly Phe Gln Arg Asn Met Lys Asn Arg Gln Cys Glu Asp Leu 3870 3875 3880 aat gaa tgt ttg gtg ttt ggc aca tgt tcc cat caa tgt ata aat 12552 Asn Glu Cys Leu Val Phe Gly Thr Cys Ser His Gln Cys Ile Asn 3885 3890 3895 gtg gaa gga tca tat aaa tgt gtg tgt gac cag aat ttt caa gaa 12597 Val Glu Gly Ser Tyr Lys Cys Val Cys Asp Gln Asn Phe Gln Glu 3900 3905 3910 aga aat aac acc tgc ata gca gaa ggc tct gaa gat caa gtt ctc 12642 Arg Asn Asn Thr Cys Ile Ala Glu Gly Ser Glu Asp Gln Val Leu 3915 3920 3925 tac att gct aat gac act gat atc ctg ggt ttt ata tat cca ttc 12687 Tyr Ile Ala Asn Asp Thr Asp Ile Leu Gly Phe Ile Tyr Pro Phe 3930 3935 3940 aac tac agt ggc gat cat caa caa att tct cat att gaa cat aat 12732 Asn Tyr Ser Gly Asp His Gln Gln Ile Ser His Ile Glu His Asn 3945 3950 3955 tca aga ata aca ggg atg gat gta tat tat caa aga gat atg att 12777 Ser Arg Ile Thr Gly Met Asp Val Tyr Tyr Gln Arg Asp Met Ile 3960 3965 3970 att tgg agt act cag ttt aat cca ggc gga att ttc tac aaa agg 12822 Ile Trp Ser Thr Gln Phe Asn Pro Gly Gly Ile Phe Tyr Lys Arg 3975 3980 3985 atc cat ggc aga gaa aaa agg caa gca aac agt ggc ttg att tgt 12867 Ile His Gly Arg Glu Lys Arg Gln Ala Asn Ser Gly Leu Ile Cys 3990 3995 4000 cct gaa ttt aaa agg ccc agg gac att gca gtt gac tgg gtg gct 12912 Pro Glu Phe Lys Arg Pro Arg Asp Ile Ala Val Asp Trp Val Ala 4005 4010 4015 gga aac att tac tgg act gat cat tct aga atg cat tgg ttc agt 12957 Gly Asn Ile Tyr Trp Thr Asp His Ser Arg Met His Trp Phe Ser 4020 4025 4030 tac tac act act cac tgg acc agt ctg agg tac tct atc aac gta 13002 Tyr Tyr Thr Thr His Trp Thr Ser Leu Arg Tyr Ser Ile Asn Val 4035 4040 4045 ggg cag ctg aat ggc ccc aac tgc acc aga ctc tta aca aat atg 13047 Gly Gln Leu Asn Gly Pro Asn Cys Thr Arg Leu Leu Thr Asn Met 4050 4055 4060 gct gga gaa ccc tat gct att gca gta aat cct aaa aga ggg atg 13092 Ala Gly Glu Pro Tyr Ala Ile Ala Val Asn Pro Lys Arg Gly Met 4065 4070 4075 atg tac tgg act gtt gtt ggg gat cat tcc cat ata gaa gaa gca 13137 Met Tyr Trp Thr Val Val Gly Asp His Ser His Ile Glu Glu Ala 4080 4085 4090 gcc atg gat ggt aca ctg aga agg att tta gta caa aag aac tta 13182 Ala Met Asp Gly Thr Leu Arg Arg Ile Leu Val Gln Lys Asn Leu 4095 4100 4105 cag aga ccc aca ggt ttg gct gtg gat tat ttt agt gaa cgc ata 13227 Gln Arg Pro Thr Gly Leu Ala Val Asp Tyr Phe Ser Glu Arg Ile 4110 4115 4120 tat tgg gct gac ttt gag ctc tcc atc att ggc agt gtt ctg tat 13272 Tyr Trp Ala Asp Phe Glu Leu Ser Ile Ile Gly Ser Val Leu Tyr 4125 4130 4135 gat ggc tct aat tca gta gtc tct gtc agc agc aaa caa ggt tta 13317 Asp Gly Ser Asn Ser Val Val Ser Val Ser Ser Lys Gln Gly Leu 4140 4145 4150 tta cat cca cat agg atc gat atc ttt gaa gat tat ata tat gga 13362 Leu His Pro His Arg Ile Asp Ile Phe Glu Asp Tyr Ile Tyr Gly 4155 4160 4165 gca gga cct aaa aat ggt gta ttt cga gtt caa aaa ttt ggc cat 13407 Ala Gly Pro Lys Asn Gly Val Phe Arg Val Gln Lys Phe Gly His 4170 4175 4180 ggt tca gta gag tac tta gct tta aat att gat aaa aca aaa ggt 13452 Gly Ser Val Glu Tyr Leu Ala Leu Asn Ile Asp Lys Thr Lys Gly 4185 4190 4195 gtt ttg ata tct cat cgt tat aaa caa cta gat tta ccc aat cca 13497 Val Leu Ile Ser His Arg Tyr Lys Gln Leu Asp Leu Pro Asn Pro 4200 4205 4210 tgc ttg gat tta gca tgc gaa ttt ctt tgc ttg cta aat cct tct 13542 Cys Leu Asp Leu Ala Cys Glu Phe Leu Cys Leu Leu Asn Pro Ser 4215 4220 4225 ggg gcc act tgt gtg tgt cca gaa gga aaa tat ttg att aat ggc 13587 Gly Ala Thr Cys Val Cys Pro Glu Gly Lys Tyr Leu Ile Asn Gly 4230 4235 4240 acc tgc aat gat gac agc ctg tta gat gat tca tgt aag tta act 13632 Thr Cys Asn Asp Asp Ser Leu Leu Asp Asp Ser Cys Lys Leu Thr 4245 4250 4255 tgt gaa aat gga gga aga tgc att tta aat gag aaa ggt gat ttg 13677 Cys Glu Asn Gly Gly Arg Cys Ile Leu Asn Glu Lys Gly Asp Leu 4260 4265 4270 agg tgt cac tgt tgg ccc agt tat tca gga gaa aga tgt gaa gtc 13722 Arg Cys His Cys Trp Pro Ser Tyr Ser Gly Glu Arg Cys Glu Val 4275 4280 4285 aac cac tgt agc aac tac tgc cag aat gga gga act tgc gta cca 13767 Asn His Cys Ser Asn Tyr Cys Gln Asn Gly Gly Thr Cys Val Pro 4290 4295 4300 tca gtt cta ggg aga ccc acc tgc agc tgt gca ctg ggt ttc act 13812 Ser Val Leu Gly Arg Pro Thr Cys Ser Cys Ala Leu Gly Phe Thr 4305 4310 4315 ggg cca aac tgt ggt aag aca gtc tgt gag gat ttt tgt caa aat 13857 Gly Pro Asn Cys Gly Lys Thr Val Cys Glu Asp Phe Cys Gln Asn 4320 4325 4330 gga gga acc tgc att gtg act gct gga aac cag cct tac tgc cac 13902 Gly Gly Thr Cys Ile Val Thr Ala Gly Asn Gln Pro Tyr Cys His 4335 4340 4345 tgc cag ccg gaa tac acc gga gac aga tgt cag tac tac gtg tgc 13947 Cys Gln Pro Glu Tyr Thr Gly Asp Arg Cys Gln Tyr Tyr Val Cys 4350 4355 4360 cac cac tat tgt gtg aat tct gaa tca tgt acc att ggg gat gat 13992 His His Tyr Cys Val Asn Ser Glu Ser Cys Thr Ile Gly Asp Asp 4365 4370 4375 gga agt ctt gaa tgt gtc tgt cca acg cgc tat gaa gga cca aaa 14037 Gly Ser Leu Glu Cys Val Cys Pro Thr Arg Tyr Glu Gly Pro Lys 4380 4385 4390 tgt gag gtt gac aag tgt gta agg tgc cat ggg ggg cac tgc att 14082 Cys Glu Val Asp Lys Cys Val Arg Cys His Gly Gly His Cys Ile 4395 4400 4405 ata aat aaa gac agt gaa gat ata ttt tgc aac tgc act aat gga 14127 Ile Asn Lys Asp Ser Glu Asp Ile Phe Cys Asn Cys Thr Asn Gly 4410 4415 4420 aag att gcc tct agc tgt cag tta tgt gat ggc tac tgt tac aat 14172 Lys Ile Ala Ser Ser Cys Gln Leu Cys Asp Gly Tyr Cys Tyr Asn 4425 4430 4435 ggt ggc aca tgc cag ctg gac ccc gag aca aat gta cct gtg tgt 14217 Gly Gly Thr Cys Gln Leu Asp Pro Glu Thr Asn Val Pro Val Cys 4440 4445 4450 cta tgc tcc acc aac tgg tca ggc aca cag tgt gaa agg cca gcc 14262 Leu Cys Ser Thr Asn Trp Ser Gly Thr Gln Cys Glu Arg Pro Ala 4455 4460 4465 cca aag agc agc aag tct gat cat atc agc aca aga agc att gcc 14307 Pro Lys Ser Ser Lys Ser Asp His Ile Ser Thr Arg Ser Ile Ala 4470 4475 4480 atc att gtg cct ctc gtc ctc ttg gtg act ttg ata acc acc tta 14352 Ile Ile Val Pro Leu Val Leu Leu Val Thr Leu Ile Thr Thr Leu 4485 4490 4495 gta att ggt tta gtg ctt tgt aaa aga aaa aga agg aca aaa aca 14397 Val Ile Gly Leu Val Leu Cys Lys Arg Lys Arg Arg Thr Lys Thr 4500 4505 4510 att aga aga caa cct att atc aat gga gga ata aat gta gaa att 14442 Ile Arg Arg Gln Pro Ile Ile Asn Gly Gly Ile Asn Val Glu Ile 4515 4520 4525 ggc aat cca tct tat aac atg tat gag gta gat cat gat cac aac 14487 Gly Asn Pro Ser Tyr Asn Met Tyr Glu Val Asp His Asp His Asn 4530 4535 4540 gat gga ggt ctt tta gat cct ggc ttt atg ata gac cca aca aag 14532 Asp Gly Gly Leu Leu Asp Pro Gly Phe Met Ile Asp Pro Thr Lys 4545 4550 4555 gcc agg tac ata ggg gga gga ccc agt gct ttc aag ctt cca cac 14577 Ala Arg Tyr Ile Gly Gly Gly Pro Ser Ala Phe Lys Leu Pro His 4560 4565 4570 aca gcg ccg ccc atc tac cta aac tct gat ttg aaa gga cca cta 14622 Thr Ala Pro Pro Ile Tyr Leu Asn Ser Asp Leu Lys Gly Pro Leu 4575 4580 4585 act gct ggg cca aca aat tac tcc aat ccg gta tat gca aaa tta 14667 Thr Ala Gly Pro Thr Asn Tyr Ser Asn Pro Val Tyr Ala Lys Leu 4590 4595 4600 tat atg gat ggg caa aac tgt cga aac tcc tta gga agt gtt gat 14712 Tyr Met Asp Gly Gln Asn Cys Arg Asn Ser Leu Gly Ser Val Asp 4605 4610 4615 gaa agg aaa gaa ctg ctt cca aag aaa ata gaa att ggt ata aga 14757 Glu Arg Lys Glu Leu Leu Pro Lys Lys Ile Glu Ile Gly Ile Arg 4620 4625 4630 gag aca gtg gca taatcagtga tatcttttat atgctgtata aatgtataag 14809 Glu Thr Val Ala 4635 aatattagga gtacatttgg tatgtcccaa caggtattat acgtggttgg catcagcatt 14869 acctctttct ttatcttttt cctggttaat tgttttctga gttttttggg ttttattttt 14929 tgctgatgac tattgattga ccatttgtat ggtattttta tgaaaaagaa ctgcactaca 14989 gtacaattta caacaatgct gctgatatga cacacctttg aatttgttaa aattaaaaac 15049 aacgtattcc tttgtagtgt gaatatgagc aatctatttt atatgaactt ttttggttgt 15109 acttaatcaa cgaggagaat ctctgcactt ttccattata cggtttgaag gctgtaatac 15169 agtgtcattt tatttttctg tttaaattga tggaaaaatg attgaatggt caactctctt 15229 ctttgtgccc ataaagatcg attcagactc tgctgaaaat atatagctct cacaagttca 15289 gcatcacctg ctttgaaatt agccttagat tgccaaccaa tagatgagaa ttttgaggaa 15349 aaaaattaaa aatatgtaaa attaataatt tgcatgaaca cagatgacta cattttccaa 15409 aacttagtgg actctatgtg atgtactaaa tgtatacacc ttgtaagcaa tagttatatt 15469 taggtggtag aacatagcaa aaatataacc gaaagttggc cgactgcact tgctatggaa 15529 taagaccttt tattctccct cagtctcgag ataaatagcc agcctagagc acaacagggc 15589 attgggtact tgcatcttag gtatttcttc ccagtcacat ccattttgtg gaagattaac 15649 ccaacccctt acactacact gaacactaaa gaataacata taagcacaca aattggtgac 15709 agaatttcaa ttacgtgaac gcatcctctt tgctaggtca aaaacaaagg gcaaagcaga 15769 cattttagta tacagagtga ttggcaaata ttttcaagat ttaatatgag caacccatta 15829 tttgccctat ccaaaatata ttcaagggcc ttccaagttg tagaagaaca atgatcttcc 15889 cataatcaaa agtggagagt cgaaatgctg tgccagttgc tctggtattc aggtttctct 15949 gggttttaca gaacgcatgg accccattca cgtttggttt gtttatcttc aaatttgagt 16009 tgaaacgagt gcgatttatt taagttgtat ataaaaataa aaggatagca tttttataca 16069 aatatcttta aaggcacaaa agatttattc acaagttttg gagggctttt tgttcctctg 16129 atagacatga ctgactttta gctgtcataa tgtattaacc taacagatga aatatgttaa 16189 atatgtggtt gctctttatc cctttgtaca agcattaaaa aaactgctgt tttataagaa 16249 gactttttgt tgtactatgt gcatgcatac tacctatttc taaactttgc catattgagg 16309 cctttataaa ctattgattt atgtaatact agtgcaattt tgcttgaaca atgttatgca 16369 tatcataaac tttttcaggt tcttgtttaa gtacattttt taaattgaac agtatttttc 16429 attttggtta taatatagtc attttgccta tgtttctaca atgaagtgtt aaatacttta 16489 taaaaaattg ttgactgact tatttaaatg aaattctaca tatttaaaaa aaaaaa 16545 <210> SEQ ID NO 33 <211> LENGTH: 4636 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 33 Met Thr Pro Leu Gly Ser Arg Leu Gln Ala Ala Pro Ala Ala Ala Ala 1 5 10 15 Ala Ala Gly Pro Lys Val Pro Pro Ser Ser Leu Gln Arg Arg Leu Pro 20 25 30 Tyr Arg Ala Thr Thr Met Ser Glu Phe Leu Leu Ala Leu Leu Thr Leu 35 40 45 Ser Gly Leu Leu Pro Ile Ala Arg Val Leu Thr Val Gly Ala Asp Arg 50 55 60 Asp Gln Gln Leu Cys Asp Pro Gly Glu Phe Leu Cys His Asp His Val 65 70 75 80 Thr Cys Val Ser Arg Ser Trp Leu Cys Asp Gly Asp Pro Asp Cys Pro 85 90 95 Asp Asp Ser Asp Glu Ser Leu Asp Thr Cys Pro Glu Glu Val Glu Ile 100 105 110 Lys Cys Pro Leu Asn His Ile Ala Cys Leu Gly Thr Asn Lys Cys Val 115 120 125 His Leu Ser Gln Leu Cys Asn Gly Val Leu Asp Cys Pro Asp Gly Tyr 130 135 140 Asp Glu Gly Val His Cys Gln Glu Leu Leu Ser Asn Cys Gln Gln Leu 145 150 155 160 Asn Cys Gln Tyr Lys Cys Thr Met Val Arg Asn Ser Thr Arg Cys Tyr 165 170 175 Cys Glu Asp Gly Phe Glu Ile Thr Glu Asp Gly Arg Ser Cys Lys Asp 180 185 190 Gln Asp Glu Cys Ala Val Tyr Gly Thr Cys Ser Gln Thr Cys Arg Asn 195 200 205 Thr His Gly Ser Tyr Thr Cys Ser Cys Val Glu Gly Tyr Leu Met Gln 210 215 220 Pro Asp Asn Arg Ser Cys Lys Ala Lys Ile Glu Pro Thr Asp Arg Pro 225 230 235 240 Pro Ile Leu Leu Ile Ala Asn Phe Glu Thr Ile Glu Val Phe Tyr Leu 245 250 255 Asn Gly Ser Lys Met Ala Thr Leu Ser Ser Val Asn Gly Asn Glu Ile 260 265 270 His Thr Leu Asp Phe Ile Tyr Asn Glu Asp Val Ile Cys Trp Ile Glu 275 280 285 Ser Arg Glu Ser Ser Asn Gln Leu Lys Cys Ile Gln Ile Thr Lys Ala 290 295 300 Gly Gly Leu Thr Asp Glu Trp Thr Ile Asn Ile Leu Gln Ser Phe His 305 310 315 320 Asn Val Gln Gln Met Ala Ile Asp Trp Leu Thr Arg Asn Leu Tyr Phe 325 330 335 Val Asp His Val Gly Asp Arg Ile Phe Val Cys Asn Ser Asn Gly Ser 340 345 350 Val Cys Val Thr Leu Ile Asp Leu Glu Leu His Asn Pro Lys Ala Ile 355 360 365 Ala Val Asp Pro Ile Ala Gly Lys Leu Phe Phe Thr Asp Tyr Gly Asn 370 375 380 Val Ala Lys Val Glu Arg Cys Asp Met Asp Gly Met Asn Arg Thr Arg 385 390 395 400 Ile Ile Asp Ser Lys Thr Glu Gln Pro Ala Ala Leu Ala Leu Asp Leu 405 410 415 Val Asn Lys Leu Val Tyr Trp Val Asp Leu Tyr Leu Asp Tyr Val Gly 420 425 430 Val Val Asp Tyr Gln Gly Lys Asn Arg His Thr Val Ile Gln Gly Arg 435 440 445 Gln Val Arg His Leu Tyr Gly Ile Thr Val Phe Glu Asp Tyr Leu Tyr 450 455 460 Ala Thr Asn Ser Asp Asn Tyr Asn Ile Val Arg Ile Asn Arg Phe Asn 465 470 475 480 Gly Thr Asp Ile His Ser Leu Ile Lys Ile Glu Asn Ala Trp Gly Ile 485 490 495 Arg Ile Tyr Gln Lys Arg Thr Gln Pro Thr Val Arg Ser His Ala Cys 500 505 510 Glu Val Asp Pro Tyr Gly Met Pro Gly Gly Cys Ser His Ile Cys Leu 515 520 525 Leu Ser Ser Ser Tyr Lys Thr Arg Thr Cys Arg Cys Arg Thr Gly Phe 530 535 540 Asn Leu Gly Ser Asp Gly Arg Ser Cys Lys Arg Pro Lys Asn Glu Leu 545 550 555 560 Phe Leu Phe Tyr Gly Lys Gly Arg Pro Gly Ile Val Arg Gly Met Asp 565 570 575 Leu Asn Thr Lys Ile Ala Asp Glu Tyr Met Ile Pro Ile Glu Asn Leu 580 585 590 Val Asn Pro Arg Ala Leu Asp Phe His Ala Glu Thr Asn Tyr Ile Tyr 595 600 605 Phe Ala Asp Thr Thr Ser Phe Leu Ile Gly Arg Gln Lys Ile Asp Gly 610 615 620 Thr Glu Arg Glu Thr Ile Leu Lys Asp Asp Leu Asp Asn Val Glu Gly 625 630 635 640 Ile Ala Val Asp Trp Ile Gly Asn Asn Leu Tyr Trp Thr Asn Asp Gly 645 650 655 His Arg Lys Thr Ile Asn Val Ala Arg Leu Glu Lys Ala Ser Gln Ser 660 665 670 Arg Lys Thr Leu Leu Glu Gly Glu Met Ser His Pro Arg Gly Ile Val 675 680 685 Val Asp Pro Ile Asn Gly Trp Met Tyr Trp Thr Asp Trp Glu Glu Asp 690 695 700 Glu Ile Asp Asp Ser Val Gly Arg Ile Glu Lys Ala Trp Met Asp Gly 705 710 715 720 Phe Asn Arg Gln Ile Phe Val Thr Ser Lys Met Leu Trp Pro Asn Gly 725 730 735 Leu Thr Leu Asp Phe His Thr Asn Thr Leu Tyr Trp Cys Asp Ala Tyr 740 745 750 Tyr Asp His Ile Glu Lys Val Phe Leu Asn Gly Thr His Arg Lys Ile 755 760 765 Val Tyr Ser Gly Arg Glu Leu Asn His Pro Phe Gly Leu Ser His His 770 775 780 Gly Asn Tyr Val Phe Trp Thr Asp Tyr Met Asn Gly Ser Ile Phe Gln 785 790 795 800 Leu Asp Leu Ile Thr Ser Glu Val Thr Leu Leu Arg His Glu Arg Pro 805 810 815 Pro Leu Phe Gly Leu Gln Ile Tyr Asp Pro Arg Lys Gln Gln Gly Asp 820 825 830 Asn Met Cys Arg Val Asn Asn Gly Gly Cys Ser Thr Leu Cys Leu Ala 835 840 845 Ile Pro Gly Gly Arg Val Cys Ala Cys Ala Asp Asn Gln Leu Leu Asp 850 855 860 Glu Asn Gly Thr Thr Cys Thr Phe Asn Pro Gly Glu Ala Leu Pro His 865 870 875 880 Ile Cys Lys Ala Gly Glu Phe Arg Cys Lys Asn Arg His Cys Ile Gln 885 890 895 Ala Arg Trp Lys Cys Asp Gly Asp Asp Asp Cys Leu Asp Gly Ser Asp 900 905 910 Glu Asp Ser Val Asn Cys Phe Asn His Ser Cys Pro Asp Asp Gln Phe 915 920 925 Lys Cys Gln Asn Asn Arg Cys Ile Pro Lys Arg Trp Leu Cys Asp Gly 930 935 940 Ala Asn Asp Cys Gly Ser Asn Glu Asp Glu Ser Asn Gln Thr Cys Thr 945 950 955 960 Ala Arg Thr Cys Gln Val Asp Gln Phe Ser Cys Gly Asn Gly Arg Cys 965 970 975 Ile Pro Arg Ala Trp Leu Cys Asp Arg Glu Asp Asp Cys Gly Asp Gln 980 985 990 Thr Asp Glu Met Ala Ser Cys Glu Phe Pro Thr Cys Glu Pro Leu Thr 995 1000 1005 Gln Phe Val Cys Lys Ser Gly Arg Cys Ile Ser Ser Lys Trp His 1010 1015 1020 Cys Asp Ser Asp Asp Asp Cys Gly Asp Gly Ser Asp Glu Val Gly 1025 1030 1035 Cys Val His Ser Cys Phe Asp Asn Gln Phe Arg Cys Ser Ser Gly 1040 1045 1050 Arg Cys Ile Pro Gly His Trp Ala Cys Asp Gly Asp Asn Asp Cys 1055 1060 1065 Gly Asp Phe Ser Asp Glu Ala Gln Ile Asn Cys Thr Lys Glu Glu 1070 1075 1080 Ile His Ser Pro Ala Gly Cys Asn Gly Asn Glu Phe Gln Cys His 1085 1090 1095 Pro Asp Gly Asn Cys Val Pro Asp Leu Trp Arg Cys Asp Gly Glu 1100 1105 1110 Lys Asp Cys Glu Asp Gly Ser Asp Glu Lys Gly Cys Asn Gly Thr 1115 1120 1125 Ile Arg Leu Cys Asp His Lys Thr Lys Phe Ser Cys Trp Ser Thr 1130 1135 1140 Gly Arg Cys Ile Asn Lys Ala Trp Val Cys Asp Gly Asp Ile Asp 1145 1150 1155 Cys Glu Asp Gln Ser Asp Glu Asp Asp Cys Asp Ser Phe Leu Cys 1160 1165 1170 Gly Pro Pro Lys His Pro Cys Ala Asn Asp Thr Ser Val Cys Leu 1175 1180 1185 Gln Pro Glu Lys Leu Cys Asn Gly Lys Lys Asp Cys Pro Asp Gly 1190 1195 1200 Ser Asp Glu Gly Tyr Leu Cys Asp Glu Cys Ser Leu Asn Asn Gly 1205 1210 1215 Gly Cys Ser Asn His Cys Ser Val Val Pro Gly Arg Gly Ile Val 1220 1225 1230 Cys Ser Cys Pro Glu Gly Leu Gln Leu Asn Lys Asp Asn Lys Thr 1235 1240 1245 Cys Glu Ile Val Asp Tyr Cys Ser Asn His Leu Lys Cys Ser Gln 1250 1255 1260 Val Cys Glu Gln His Lys His Thr Val Lys Cys Ser Cys Tyr Glu 1265 1270 1275 Gly Trp Lys Leu Asp Val Asp Gly Glu Ser Cys Thr Ser Val Asp 1280 1285 1290 Pro Phe Glu Ala Phe Ile Ile Phe Ser Ile Arg His Glu Ile Arg 1295 1300 1305 Arg Ile Asp Leu His Lys Arg Asp Tyr Ser Leu Leu Val Pro Gly 1310 1315 1320 Leu Arg Asn Thr Ile Ala Leu Asp Phe His Phe Asn Gln Ser Leu 1325 1330 1335 Leu Tyr Trp Thr Asp Val Val Glu Asp Arg Ile Tyr Arg Gly Lys 1340 1345 1350 Leu Ser Glu Ser Gly Gly Val Ser Ala Ile Glu Val Val Val Glu 1355 1360 1365 His Gly Leu Ala Thr Pro Glu Gly Leu Thr Val Asp Trp Ile Ala 1370 1375 1380 Gly Asn Ile Tyr Trp Ile Asp Ser Asn Leu Asp Gln Ile Glu Val 1385 1390 1395 Ala Lys Leu Asp Gly Ser Leu Arg Thr Thr Leu Ile Ala Gly Ala 1400 1405 1410 Met Glu His Pro Arg Ala Ile Ala Leu Asp Pro Arg Tyr Gly Ile 1415 1420 1425 Leu Phe Trp Thr Asp Trp Asp Ala Asn Phe Pro Arg Ile Glu Ser 1430 1435 1440 Ala Ser Met Ser Gly Ala Gly Arg Lys Thr Ile Tyr Lys Asp Met 1445 1450 1455 Lys Thr Gly Ala Trp Pro Asn Gly Leu Thr Val Asp His Phe Glu 1460 1465 1470 Lys Arg Ile Val Trp Thr Asp Ala Arg Ser Asp Ala Ile Tyr Ser 1475 1480 1485 Ala Leu Tyr Asp Gly Thr Asn Met Ile Glu Ile Ile Arg Gly His 1490 1495 1500 Glu Tyr Leu Ser His Pro Phe Ala Val Ser Leu Tyr Gly Ser Glu 1505 1510 1515 Val Tyr Trp Thr Asp Trp Arg Thr Asn Thr Leu Ser Lys Ala Asn 1520 1525 1530 Lys Trp Thr Gly Gln Asn Val Ser Val Ile Gln Lys Thr Ser Ala 1535 1540 1545 Gln Pro Phe Asp Leu Gln Ile Tyr His Pro Ser Arg Gln Pro Gln 1550 1555 1560 Ala Pro Asn Pro Cys Ala Ala Asn Asp Gly Lys Gly Pro Cys Ser 1565 1570 1575 His Met Cys Leu Ile Asn His Asn Arg Ser Ala Ala Cys Ala Cys 1580 1585 1590 Pro His Leu Met Lys Leu Ser Ser Asp Lys Lys Thr Cys Tyr Glu 1595 1600 1605 Met Lys Lys Phe Leu Leu Tyr Ala Arg Arg Ser Glu Ile Arg Gly 1610 1615 1620 Val Asp Ile Asp Asn Pro Tyr Phe Asn Phe Ile Thr Ala Phe Thr 1625 1630 1635 Val Pro Asp Ile Asp Asp Val Thr Val Ile Asp Phe Asp Ala Ser 1640 1645 1650 Glu Glu Arg Leu Tyr Trp Thr Asp Ile Lys Thr Gln Thr Ile Lys 1655 1660 1665 Arg Ala Phe Ile Asn Gly Thr Gly Leu Glu Thr Val Ile Ser Arg 1670 1675 1680 Asp Ile Gln Ser Ile Arg Gly Leu Ala Val Asp Trp Val Ser Arg 1685 1690 1695 Asn Leu Tyr Trp Ile Ser Ser Glu Phe Asp Glu Thr Gln Ile Asn 1700 1705 1710 Val Ala Arg Leu Asp Gly Ser Leu Lys Thr Ser Ile Ile His Gly 1715 1720 1725 Ile Asp Lys Pro Gln Cys Leu Ala Ala His Pro Val Arg Gly Lys 1730 1735 1740 Leu Tyr Trp Thr Asp Gly Asn Thr Ile Asn Met Ala Asn Met Asp 1745 1750 1755 Gly Ser Asn Ser Lys Ile Leu Phe Gln Asn Gln Lys Glu Pro Val 1760 1765 1770 Gly Leu Ser Ile Asp Tyr Val Glu Asn Lys Leu Tyr Trp Ile Ser 1775 1780 1785 Ser Gly Asn Gly Thr Ile Asn Arg Cys Asn Leu Asp Gly Gly Asn 1790 1795 1800 Leu Glu Val Ile Glu Ser Met Lys Glu Glu Leu Thr Lys Ala Thr 1805 1810 1815 Ala Leu Thr Ile Met Asp Lys Lys Leu Trp Trp Ala Asp Gln Asn 1820 1825 1830 Leu Ala Gln Leu Gly Thr Cys Ser Lys Arg Asp Gly Arg Asn Pro 1835 1840 1845 Thr Ile Leu Arg Asn Lys Thr Ser Gly Val Val His Met Lys Val 1850 1855 1860 Tyr Asp Lys Glu Ala Gln Gln Gly Ser Asn Ser Cys Gln Leu Asn 1865 1870 1875 Asn Gly Gly Cys Ser Gln Leu Cys Leu Pro Thr Ser Glu Thr Thr 1880 1885 1890 Arg Thr Cys Met Cys Thr Val Gly Tyr Tyr Leu Gln Lys Asn Arg 1895 1900 1905 Met Ser Cys Gln Gly Ile Glu Ser Phe Leu Met Tyr Ser Val His 1910 1915 1920 Glu Gly Ile Arg Gly Ile Pro Leu Glu Pro Ser Asp Lys Met Asp 1925 1930 1935 Ala Leu Met Pro Ile Ser Gly Thr Ser Phe Ala Val Gly Ile Asp 1940 1945 1950 Phe His Ala Glu Asn Asp Thr Ile Tyr Trp Thr Asp Met Gly Phe 1955 1960 1965 Asn Lys Ile Ser Arg Ala Lys Arg Asp Gln Thr Trp Lys Glu Asp 1970 1975 1980 Ile Ile Thr Asn Gly Leu Gly Arg Val Glu Gly Ile Ala Val Asp 1985 1990 1995 Trp Ile Ala Gly Asn Ile Tyr Trp Thr Asp His Gly Phe Asn Leu 2000 2005 2010 Ile Glu Val Ala Arg Leu Asn Gly Ser Phe Arg Tyr Val Ile Ile 2015 2020 2025 Ser Gln Gly Leu Asp Gln Pro Arg Ser Ile Ala Val His Pro Glu 2030 2035 2040 Lys Gly Leu Leu Phe Trp Thr Glu Trp Gly Gln Met Pro Cys Ile 2045 2050 2055 Gly Lys Ala Arg Leu Asp Gly Ser Glu Lys Val Val Leu Val Ser 2060 2065 2070 Met Gly Ile Ala Trp Pro Asn Gly Ile Ser Ile Asp Tyr Glu Glu 2075 2080 2085 Asn Lys Leu Tyr Trp Cys Asp Ala Arg Thr Asp Lys Ile Glu Arg 2090 2095 2100 Ile Asp Leu Glu Thr Gly Gly Asn Arg Glu Met Val Leu Ser Gly 2105 2110 2115 Ser Asn Val Asp Met Phe Ser Val Ala Val Phe Gly Ala Tyr Ile 2120 2125 2130 Tyr Trp Ser Asp Arg Ala His Ala Asn Gly Ser Val Arg Arg Gly 2135 2140 2145 His Lys Asn Asp Ala Thr Glu Thr Ile Thr Met Arg Thr Gly Leu 2150 2155 2160 Gly Val Asn Leu Lys Glu Val Lys Ile Phe Asn Arg Val Arg Glu 2165 2170 2175 Lys Gly Thr Asn Val Cys Ala Arg Asp Asn Gly Gly Cys Lys Gln 2180 2185 2190 Leu Cys Leu Tyr Arg Gly Asn Ser Arg Arg Thr Cys Ala Cys Ala 2195 2200 2205 His Gly Tyr Leu Ala Glu Asp Gly Val Thr Cys Leu Arg His Glu 2210 2215 2220 Gly Tyr Leu Leu Tyr Ser Gly Arg Thr Ile Leu Lys Ser Ile His 2225 2230 2235 Leu Ser Asp Glu Thr Asn Leu Asn Ser Pro Ile Arg Pro Tyr Glu 2240 2245 2250 Asn Pro Arg Tyr Phe Lys Asn Val Ile Ala Leu Ala Phe Asp Tyr 2255 2260 2265 Asn Gln Arg Arg Lys Gly Thr Asn Arg Ile Phe Tyr Ser Asp Ala 2270 2275 2280 His Phe Gly Asn Ile Gln Leu Ile Lys Asp Asn Trp Glu Asp Arg 2285 2290 2295 Gln Val Ile Val Glu Asn Val Gly Ser Val Glu Gly Leu Ala Tyr 2300 2305 2310 His Arg Ala Trp Asp Thr Leu Tyr Trp Thr Ser Ser Thr Thr Ser 2315 2320 2325 Ser Ile Thr Arg His Thr Val Asp Gln Thr Arg Pro Gly Ala Phe 2330 2335 2340 Asp Arg Glu Ala Val Ile Thr Met Ser Glu Asp Asp His Pro His 2345 2350 2355 Val Leu Ala Leu Asp Glu Cys Gln Asn Leu Met Phe Trp Thr Asn 2360 2365 2370 Trp Asn Glu Gln His Pro Ser Ile Met Arg Ser Thr Leu Thr Gly 2375 2380 2385 Lys Asn Ala Gln Val Val Val Ser Thr Asp Ile Leu Thr Pro Asn 2390 2395 2400 Gly Leu Thr Ile Asp Tyr Arg Ala Glu Lys Leu Tyr Phe Ser Asp 2405 2410 2415 Gly Ser Leu Gly Lys Ile Glu Arg Cys Glu Tyr Asp Gly Ser Gln 2420 2425 2430 Arg His Val Ile Val Lys Ser Gly Pro Gly Thr Phe Leu Ser Leu 2435 2440 2445 Ala Val Tyr Asp Asn Tyr Ile Phe Trp Ser Asp Trp Gly Arg Arg 2450 2455 2460 Ala Ile Leu Arg Ser Asn Lys Tyr Thr Gly Gly Asp Thr Lys Ile 2465 2470 2475 Leu Arg Ser Asp Ile Pro His Gln Pro Met Gly Ile Ile Ala Val 2480 2485 2490 Ala Asn Asp Thr Asn Ser Cys Glu Leu Ser Pro Cys Ala Leu Leu 2495 2500 2505 Asn Gly Gly Cys His Asp Leu Cys Leu Leu Thr Pro Asn Gly Arg 2510 2515 2520 Val Asn Cys Ser Cys Arg Gly Asp Arg Ile Leu Leu Glu Asp Asn 2525 2530 2535 Arg Cys Val Thr Lys Asn Ser Ser Cys Asn Ala Tyr Ser Glu Phe 2540 2545 2550 Glu Cys Gly Asn Gly Glu Cys Ile Asp Tyr Gln Leu Thr Cys Asp 2555 2560 2565 Gly Ile Pro His Cys Lys Asp Lys Ser Asp Glu Lys Leu Leu Tyr 2570 2575 2580 Cys Glu Asn Arg Ser Cys Arg Arg Gly Phe Lys Pro Cys Tyr Asn 2585 2590 2595 Arg Arg Cys Ile Pro His Gly Lys Leu Cys Asp Gly Glu Asn Asp 2600 2605 2610 Cys Gly Asp Asn Ser Asp Glu Leu Asp Cys Lys Val Ser Thr Cys 2615 2620 2625 Ala Thr Val Glu Phe Arg Cys Ala Asp Gly Thr Cys Ile Pro Arg 2630 2635 2640 Ser Ala Arg Cys Asn Gln Asn Ile Asp Cys Ala Asp Ala Ser Asp 2645 2650 2655 Glu Lys Asn Cys Asn Asn Thr Asp Cys Thr His Phe Tyr Lys Leu 2660 2665 2670 Gly Val Lys Thr Thr Gly Phe Ile Arg Cys Asn Ser Thr Ser Leu 2675 2680 2685 Cys Val Leu Pro Thr Trp Ile Cys Asp Gly Ser Asn Asp Cys Gly 2690 2695 2700 Asp Tyr Ser Asp Glu Leu Lys Cys Pro Val Gln Asn Lys His Lys 2705 2710 2715 Cys Glu Glu Asn Tyr Phe Ser Cys Pro Ser Gly Arg Cys Ile Leu 2720 2725 2730 Asn Thr Trp Ile Cys Asp Gly Gln Lys Asp Cys Glu Asp Gly Arg 2735 2740 2745 Asp Glu Phe His Cys Asp Ser Ser Cys Ser Trp Asn Gln Phe Ala 2750 2755 2760 Cys Ser Ala Gln Lys Cys Ile Ser Lys His Trp Ile Cys Asp Gly 2765 2770 2775 Glu Asp Asp Cys Gly Asp Gly Leu Asp Glu Ser Asp Ser Ile Cys 2780 2785 2790 Gly Ala Ile Thr Cys Ala Ala Asp Met Phe Ser Cys Gln Gly Ser 2795 2800 2805 Arg Ala Cys Val Pro Arg His Trp Leu Cys Asp Gly Glu Arg Asp 2810 2815 2820 Cys Pro Asp Gly Ser Asp Glu Leu Ser Thr Ala Gly Cys Ala Pro 2825 2830 2835 Asn Asn Thr Cys Asp Glu Asn Ala Phe Met Cys His Asn Lys Val 2840 2845 2850 Cys Ile Pro Lys Gln Phe Val Cys Asp His Asp Asp Asp Cys Gly 2855 2860 2865 Asp Gly Ser Asp Glu Ser Pro Gln Cys Gly Tyr Arg Gln Cys Gly 2870 2875 2880 Thr Glu Glu Phe Ser Cys Ala Asp Gly Arg Cys Leu Leu Asn Thr 2885 2890 2895 Gln Trp Gln Cys Asp Gly Asp Phe Asp Cys Pro Asp His Ser Asp 2900 2905 2910 Glu Ala Pro Leu Asn Pro Lys Cys Lys Ser Ala Glu Gln Ser Cys 2915 2920 2925 Asn Ser Ser Phe Phe Met Cys Lys Asn Gly Arg Cys Ile Pro Ser 2930 2935 2940 Gly Gly Leu Cys Asp Asn Lys Asp Asp Cys Gly Asp Gly Ser Asp 2945 2950 2955 Glu Arg Asn Cys His Ile Asn Glu Cys Leu Ser Lys Lys Val Ser 2960 2965 2970 Gly Cys Ser Gln Asp Cys Gln Asp Leu Pro Val Ser Tyr Lys Cys 2975 2980 2985 Lys Cys Trp Pro Gly Phe Gln Leu Lys Asp Asp Gly Lys Thr Cys 2990 2995 3000 Val Asp Ile Asp Glu Cys Ser Ser Gly Phe Pro Cys Ser Gln Gln 3005 3010 3015 Cys Ile Asn Thr Tyr Gly Thr Tyr Lys Cys Leu Cys Thr Asp Gly 3020 3025 3030 Tyr Glu Ile Gln Pro Asp Asn Pro Asn Gly Cys Lys Ser Leu Ser 3035 3040 3045 Asp Glu Glu Pro Phe Leu Ile Leu Ala Asp His His Glu Ile Arg 3050 3055 3060 Lys Ile Ser Thr Asp Gly Ser Asn Tyr Thr Leu Leu Lys Gln Gly 3065 3070 3075 Leu Asn Asn Val Ile Ala Ile Asp Phe Asp Tyr Arg Glu Glu Phe 3080 3085 3090 Ile Tyr Trp Ile Asp Ser Ser Arg Pro Asn Gly Ser Arg Ile Asn 3095 3100 3105 Arg Met Cys Leu Asn Gly Ser Asp Ile Lys Val Val His Asn Thr 3110 3115 3120 Ala Val Pro Asn Ala Leu Ala Val Asp Trp Ile Gly Lys Asn Leu 3125 3130 3135 Tyr Trp Ser Asp Thr Glu Lys Arg Ile Ile Glu Val Ser Lys Leu 3140 3145 3150 Asn Gly Leu Tyr Pro Thr Ile Leu Val Ser Lys Arg Leu Lys Phe 3155 3160 3165 Pro Arg Asp Leu Ser Leu Asp Pro Gln Ala Gly Tyr Leu Tyr Trp 3170 3175 3180 Ile Asp Cys Cys Glu Tyr Pro His Ile Gly Arg Val Gly Met Asp 3185 3190 3195 Gly Thr Asn Gln Ser Val Val Ile Glu Thr Lys Ile Ser Arg Pro 3200 3205 3210 Met Ala Leu Thr Ile Asp Tyr Val Asn Arg Arg Leu Tyr Trp Ala 3215 3220 3225 Asp Glu Asn His Ile Glu Phe Ser Asn Met Asp Gly Ser His Arg 3230 3235 3240 His Lys Val Pro Asn Gln Asp Ile Pro Gly Val Ile Ala Leu Thr 3245 3250 3255 Leu Phe Glu Asp Tyr Ile Tyr Trp Thr Asp Gly Lys Thr Lys Ser 3260 3265 3270 Leu Ser Arg Ala His Lys Thr Ser Gly Ala Asp Arg Leu Ser Leu 3275 3280 3285 Ile Tyr Ser Trp His Ala Ile Thr Asp Ile Gln Val Tyr His Ser 3290 3295 3300 Tyr Arg Gln Pro Asp Val Ser Lys His Leu Cys Met Ile Asn Asn 3305 3310 3315 Gly Gly Cys Ser His Leu Cys Leu Leu Ala Pro Gly Lys Thr His 3320 3325 3330 Thr Cys Ala Cys Pro Thr Asn Phe Tyr Leu Ala Ala Asp Asn Arg 3335 3340 3345 Thr Cys Leu Ser Asn Cys Thr Ala Ser Gln Phe Arg Cys Lys Thr 3350 3355 3360 Asp Lys Cys Ile Pro Phe Trp Trp Lys Cys Asp Thr Val Asp Asp 3365 3370 3375 Cys Gly Asp Gly Ser Asp Glu Pro Asp Asp Cys Pro Glu Phe Arg 3380 3385 3390 Cys Gln Pro Gly Arg Phe Gln Cys Gly Thr Gly Leu Cys Ala Leu 3395 3400 3405 Pro Ala Phe Ile Cys Asp Gly Glu Asn Asp Cys Gly Asp Asn Ser 3410 3415 3420 Asp Glu Leu Asn Cys Asp Thr His Val Cys Leu Ser Gly Gln Phe 3425 3430 3435 Lys Cys Thr Lys Asn Gln Lys Cys Ile Pro Val Asn Leu Arg Cys 3440 3445 3450 Asn Gly Gln Asp Asp Cys Gly Asp Glu Glu Asp Glu Arg Asp Cys 3455 3460 3465 Pro Glu Asn Ser Cys Ser Pro Asp Tyr Phe Gln Cys Lys Thr Thr 3470 3475 3480 Lys His Cys Ile Ser Lys Leu Trp Val Cys Asp Glu Asp Pro Asp 3485 3490 3495 Cys Ala Asp Ala Ser Asp Glu Ala Asn Cys Asp Lys Lys Thr Cys 3500 3505 3510 Gly Pro His Glu Phe Gln Cys Lys Asn Asn Asn Cys Ile Pro Asp 3515 3520 3525 His Trp Arg Cys Asp Ser Gln Asn Asp Cys Ser Asp Asn Ser Asp 3530 3535 3540 Glu Glu Asn Cys Lys Pro Gln Thr Cys Thr Leu Lys Asp Phe Leu 3545 3550 3555 Cys Ala Asn Gly Asp Cys Val Ser Ser Arg Phe Trp Cys Asp Gly 3560 3565 3570 Asp Phe Asp Cys Ala Asp Gly Ser Asp Glu Arg Asn Cys Glu Thr 3575 3580 3585 Ser Cys Ser Lys Asp Gln Phe Arg Cys Ser Asn Gly Gln Cys Ile 3590 3595 3600 Pro Ala Lys Trp Lys Cys Asp Gly His Glu Asp Cys Lys Tyr Gly 3605 3610 3615 Glu Asp Glu Lys Ser Cys Glu Pro Ala Ser Pro Thr Cys Ser Ser 3620 3625 3630 Arg Glu Tyr Ile Cys Ala Ser Asp Gly Cys Ile Ser Ala Ser Leu 3635 3640 3645 Lys Cys Asn Gly Glu Tyr Asp Cys Ala Asp Gly Ser Asp Glu Met 3650 3655 3660 Asp Cys Val Thr Glu Cys Lys Glu Asp Gln Phe Arg Cys Lys Asn 3665 3670 3675 Lys Ala His Cys Ile Pro Ile Arg Trp Leu Cys Asp Gly Ile His 3680 3685 3690 Asp Cys Val Asp Gly Ser Asp Glu Glu Asn Cys Glu Arg Gly Gly 3695 3700 3705 Asn Ile Cys Arg Ala Asp Glu Phe Leu Cys Asn Asn Ser Leu Cys 3710 3715 3720 Lys Leu His Phe Trp Val Cys Asp Gly Glu Asp Asp Cys Gly Asp 3725 3730 3735 Asn Ser Asp Glu Ala Pro Asp Met Cys Val Lys Phe Leu Cys Pro 3740 3745 3750 Ser Thr Arg Pro His Arg Cys Arg Asn Asn Arg Ile Cys Leu Gln 3755 3760 3765 Ser Glu Gln Met Cys Asn Gly Ile Asp Glu Cys Gly Asp Asn Ser 3770 3775 3780 Asp Glu Asp His Cys Gly Gly Lys Leu Thr Tyr Lys Ala Arg Pro 3785 3790 3795 Cys Lys Lys Asp Glu Phe Ala Cys Ser Asn Lys Lys Cys Ile Pro 3800 3805 3810 Met Asp Leu Gln Cys Asp Arg Leu Asp Asp Cys Gly Asp Gly Ser 3815 3820 3825 Asp Glu Gln Gly Cys Arg Ile Ala Pro Thr Glu Tyr Thr Cys Glu 3830 3835 3840 Asp Asn Val Asn Pro Cys Gly Asp Asp Ala Tyr Cys Asn Gln Ile 3845 3850 3855 Lys Thr Ser Val Phe Cys Arg Cys Lys Pro Gly Phe Gln Arg Asn 3860 3865 3870 Met Lys Asn Arg Gln Cys Glu Asp Leu Asn Glu Cys Leu Val Phe 3875 3880 3885 Gly Thr Cys Ser His Gln Cys Ile Asn Val Glu Gly Ser Tyr Lys 3890 3895 3900 Cys Val Cys Asp Gln Asn Phe Gln Glu Arg Asn Asn Thr Cys Ile 3905 3910 3915 Ala Glu Gly Ser Glu Asp Gln Val Leu Tyr Ile Ala Asn Asp Thr 3920 3925 3930 Asp Ile Leu Gly Phe Ile Tyr Pro Phe Asn Tyr Ser Gly Asp His 3935 3940 3945 Gln Gln Ile Ser His Ile Glu His Asn Ser Arg Ile Thr Gly Met 3950 3955 3960 Asp Val Tyr Tyr Gln Arg Asp Met Ile Ile Trp Ser Thr Gln Phe 3965 3970 3975 Asn Pro Gly Gly Ile Phe Tyr Lys Arg Ile His Gly Arg Glu Lys 3980 3985 3990 Arg Gln Ala Asn Ser Gly Leu Ile Cys Pro Glu Phe Lys Arg Pro 3995 4000 4005 Arg Asp Ile Ala Val Asp Trp Val Ala Gly Asn Ile Tyr Trp Thr 4010 4015 4020 Asp His Ser Arg Met His Trp Phe Ser Tyr Tyr Thr Thr His Trp 4025 4030 4035 Thr Ser Leu Arg Tyr Ser Ile Asn Val Gly Gln Leu Asn Gly Pro 4040 4045 4050 Asn Cys Thr Arg Leu Leu Thr Asn Met Ala Gly Glu Pro Tyr Ala 4055 4060 4065 Ile Ala Val Asn Pro Lys Arg Gly Met Met Tyr Trp Thr Val Val 4070 4075 4080 Gly Asp His Ser His Ile Glu Glu Ala Ala Met Asp Gly Thr Leu 4085 4090 4095 Arg Arg Ile Leu Val Gln Lys Asn Leu Gln Arg Pro Thr Gly Leu 4100 4105 4110 Ala Val Asp Tyr Phe Ser Glu Arg Ile Tyr Trp Ala Asp Phe Glu 4115 4120 4125 Leu Ser Ile Ile Gly Ser Val Leu Tyr Asp Gly Ser Asn Ser Val 4130 4135 4140 Val Ser Val Ser Ser Lys Gln Gly Leu Leu His Pro His Arg Ile 4145 4150 4155 Asp Ile Phe Glu Asp Tyr Ile Tyr Gly Ala Gly Pro Lys Asn Gly 4160 4165 4170 Val Phe Arg Val Gln Lys Phe Gly His Gly Ser Val Glu Tyr Leu 4175 4180 4185 Ala Leu Asn Ile Asp Lys Thr Lys Gly Val Leu Ile Ser His Arg 4190 4195 4200 Tyr Lys Gln Leu Asp Leu Pro Asn Pro Cys Leu Asp Leu Ala Cys 4205 4210 4215 Glu Phe Leu Cys Leu Leu Asn Pro Ser Gly Ala Thr Cys Val Cys 4220 4225 4230 Pro Glu Gly Lys Tyr Leu Ile Asn Gly Thr Cys Asn Asp Asp Ser 4235 4240 4245 Leu Leu Asp Asp Ser Cys Lys Leu Thr Cys Glu Asn Gly Gly Arg 4250 4255 4260 Cys Ile Leu Asn Glu Lys Gly Asp Leu Arg Cys His Cys Trp Pro 4265 4270 4275 Ser Tyr Ser Gly Glu Arg Cys Glu Val Asn His Cys Ser Asn Tyr 4280 4285 4290 Cys Gln Asn Gly Gly Thr Cys Val Pro Ser Val Leu Gly Arg Pro 4295 4300 4305 Thr Cys Ser Cys Ala Leu Gly Phe Thr Gly Pro Asn Cys Gly Lys 4310 4315 4320 Thr Val Cys Glu Asp Phe Cys Gln Asn Gly Gly Thr Cys Ile Val 4325 4330 4335 Thr Ala Gly Asn Gln Pro Tyr Cys His Cys Gln Pro Glu Tyr Thr 4340 4345 4350 Gly Asp Arg Cys Gln Tyr Tyr Val Cys His His Tyr Cys Val Asn 4355 4360 4365 Ser Glu Ser Cys Thr Ile Gly Asp Asp Gly Ser Leu Glu Cys Val 4370 4375 4380 Cys Pro Thr Arg Tyr Glu Gly Pro Lys Cys Glu Val Asp Lys Cys 4385 4390 4395 Val Arg Cys His Gly Gly His Cys Ile Ile Asn Lys Asp Ser Glu 4400 4405 4410 Asp Ile Phe Cys Asn Cys Thr Asn Gly Lys Ile Ala Ser Ser Cys 4415 4420 4425 Gln Leu Cys Asp Gly Tyr Cys Tyr Asn Gly Gly Thr Cys Gln Leu 4430 4435 4440 Asp Pro Glu Thr Asn Val Pro Val Cys Leu Cys Ser Thr Asn Trp 4445 4450 4455 Ser Gly Thr Gln Cys Glu Arg Pro Ala Pro Lys Ser Ser Lys Ser 4460 4465 4470 Asp His Ile Ser Thr Arg Ser Ile Ala Ile Ile Val Pro Leu Val 4475 4480 4485 Leu Leu Val Thr Leu Ile Thr Thr Leu Val Ile Gly Leu Val Leu 4490 4495 4500 Cys Lys Arg Lys Arg Arg Thr Lys Thr Ile Arg Arg Gln Pro Ile 4505 4510 4515 Ile Asn Gly Gly Ile Asn Val Glu Ile Gly Asn Pro Ser Tyr Asn 4520 4525 4530 Met Tyr Glu Val Asp His Asp His Asn Asp Gly Gly Leu Leu Asp 4535 4540 4545 Pro Gly Phe Met Ile Asp Pro Thr Lys Ala Arg Tyr Ile Gly Gly 4550 4555 4560 Gly Pro Ser Ala Phe Lys Leu Pro His Thr Ala Pro Pro Ile Tyr 4565 4570 4575 Leu Asn Ser Asp Leu Lys Gly Pro Leu Thr Ala Gly Pro Thr Asn 4580 4585 4590 Tyr Ser Asn Pro Val Tyr Ala Lys Leu Tyr Met Asp Gly Gln Asn 4595 4600 4605 Cys Arg Asn Ser Leu Gly Ser Val Asp Glu Arg Lys Glu Leu Leu 4610 4615 4620 Pro Lys Lys Ile Glu Ile Gly Ile Arg Glu Thr Val Ala 4625 4630 4635 <210> SEQ ID NO 34 <211> LENGTH: 2242 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (2223) <223> OTHER INFORMATION: n = a, c, g, or t <400> SEQUENCE: 34 gaatgccttt tagtgccttg cttcctgaac tagctcacag tagcccggcg gcccagggca 60 atccgaccac atttcactct caccgctgta ggaatccaga tgcaggccaa gtacagcagc 120 acgagggaca tgctggatga tgatggggac accaccatga gcctgcattc tcaagcctct 180 gccacaactc ggcatccaga gccccggcgc acagagcaca gggctccctc ttcaacgtgg 240 cgaccagtgg ccctgaccct gctgactttg tgcttggtgc tgctgatagg gctggcagcc 300 ctggggcttt tgttttttca gtactaccag ctctccaata ctggtcaaga caccatttct 360 caaatggaag aaagattagg aaatacgtcc caagagttgc aatctcttca agtccagaat 420 ataaagcttg caggaagtct gcagcatgtg gctgaaaaac tctgtcgtga gctgtataac 480 aaagctggag cacacaggtg cagcccttgt acagaacaat ggaaatggca tggagacaat 540 tgctaccagt tctataaaga cagcaaaagt tgggaggact gtaaatattt ctgccttagt 600 gaaaactcta ccatgctgaa gataaacaaa caagaagacc tggaatttgc cgcgtctcag 660 agctactctg agtttttcta ctcttattgg acagggcttt tgcgccctga cagtggcaag 720 gcctggctgt ggatggatgg aacccctttc acttctgaac tgttccatat tataatagat 780 gtcaccagcc caagaagcag agactgtgtg gccatcctta atgggatgat cttctcaaag 840 gactgcaaag aattgaagcg ttgtgtctgt gagagaaggg caggaatggt gaagccagag 900 agcctccatg tcccccctga aacattaggc gaaggtgact gattcgccct ctgcaactac 960 aaatagcaga gtgagccagg cggtgccaaa gcaagggcta gttgagacat tgggaaatgg 1020 aacataatca ggaaagacta tctctctgac tagtacaaaa tgggttctcg tgtttcctgt 1080 tcaggatcac cagcatttct gagcttgggt ttatgcacgt atttaacagt cacaagaagt 1140 cttatttaca tgccaccaac caacctcaga aacccataat gtcatctgcc ttcttggctt 1200 agagataact tttagctctc tttcttctca atgtctaata tcacctccct gttttcatgt 1260 cttccttaca cttggtggaa taagaaactt tttgaagtag aggaaataca ttgaggtaac 1320 atccttttct ctgacagtca agtagtccat cagaaattgg cagtcacttc ccagattgta 1380 ccagcaaata cacaaggaat tctttttgtt tgtttcagtt catactagtc ccttcccaat 1440 ccatcagtaa agaccccatc tgccttgtcc atgccgtttc ccaacaggga tgtcacttga 1500 tatgagaatc tcaaatctca atgccttata agcattcctt cctgtgtcca ttaagactct 1560 gataattgtc tcccctccat aggaatttct cccaggaaag aaatatatcc ccatctccgt 1620 ttcatatcag aactaccgtc cccgatattc ccttcagaga gattaaagac cagaaaaaag 1680 tgagcctctt catctgcacc tgtaatagtt tcagttccta ttttcttcca ttgacccata 1740 tttatacctt tcaggtactg aagatttaat aataataaat gtaaatactg tgaagtgtgt 1800 gtgattttac aatggactta tggttggtgg gaaaattcag catggaaatg cttttcaaaa 1860 tatgatagcg gtcattattt tgattgtgcc ttactgaaag tttttgggga atttacaaga 1920 gtactgatta catgattatc tggagaaaat aagatgtctt tgaaatacat gttggcttca 1980 agaaaacagt tttaacgttt tcctaaaatg aaatcttttg aggtgagctt atggcatcaa 2040 cacatggttg atgaggaagc tgagttgcat tagtgcacat gatttccagt caggtcatgg 2100 gaaatgaaca gagacagtga catctttgta gctgctcctt tgtgaggcac ttctttcttg 2160 agatgactcc atgcacaaat ataacaggga tcattgggaa tgacaccatc acagccacca 2220 agnttattgg gttactgata at 2242 <210> SEQ ID NO 35 <211> LENGTH: 280 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 35 Met Gln Ala Lys Tyr Ser Ser Thr Arg Asp Met Leu Asp Asp Asp Gly 1 5 10 15 Asp Thr Thr Met Ser Leu His Ser Gln Ala Ser Ala Thr Thr Arg His 20 25 30 Pro Glu Pro Arg Arg Thr Glu His Arg Ala Pro Ser Ser Thr Trp Arg 35 40 45 Pro Val Ala Leu Thr Leu Leu Thr Leu Cys Leu Val Leu Leu Ile Gly 50 55 60 Leu Ala Ala Leu Gly Leu Leu Phe Phe Gln Tyr Tyr Gln Leu Ser Asn 65 70 75 80 Thr Gly Gln Asp Thr Ile Ser Gln Met Glu Glu Arg Leu Gly Asn Thr 85 90 95 Ser Gln Glu Leu Gln Ser Leu Gln Val Gln Asn Ile Lys Leu Ala Gly 100 105 110 Ser Leu Gln His Val Ala Glu Lys Leu Cys Arg Glu Leu Tyr Asn Lys 115 120 125 Ala Gly Ala His Arg Cys Ser Pro Cys Thr Glu Gln Trp Lys Trp His 130 135 140 Gly Asp Asn Cys Tyr Gln Phe Tyr Lys Asp Ser Lys Ser Trp Glu Asp 145 150 155 160 Cys Lys Tyr Phe Cys Leu Ser Glu Asn Ser Thr Met Leu Lys Ile Asn 165 170 175 Lys Gln Glu Asp Leu Glu Phe Ala Ala Ser Gln Ser Tyr Ser Glu Phe 180 185 190 Phe Tyr Ser Tyr Trp Thr Gly Leu Leu Arg Pro Asp Ser Gly Lys Ala 195 200 205 Trp Leu Trp Met Asp Gly Thr Pro Phe Thr Ser Glu Leu Phe His Ile 210 215 220 Ile Ile Asp Val Thr Ser Pro Arg Ser Arg Asp Cys Val Ala Ile Leu 225 230 235 240 Asn Gly Met Ile Phe Ser Lys Asp Cys Lys Glu Leu Lys Arg Cys Val 245 250 255 Cys Glu Arg Arg Ala Gly Met Val Lys Pro Glu Ser Leu His Val Pro 260 265 270 Pro Glu Thr Leu Gly Glu Gly Asp 275 280 <210> SEQ ID NO 36 <211> LENGTH: 2323 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (2304) <223> OTHER INFORMATION: n = a, c, g, or t <400> SEQUENCE: 36 gaatgccttt tagtgccttg cttcctgaac tagctcacag tagcccggcg gcccagggca 60 atccgaccac atttcactct caccgctgta ggaatccaga tgcaggccaa gtacagcagc 120 acgagggaca tgctggatga tgatggggac accaccatga gcctgcattc tcaagcctct 180 gccacaactc ggcatccaga gccccggcgc acagagcaca gggctccctc ttcaacgtgg 240 cgaccagtgg ccctgaccct gctgactttg tgcttggtgc tgctgatagg gctggcagcc 300 ctggggcttt tgttttttca gtactaccag ctctccaata ctggtcaaga caccatttct 360 caaatggaag aaagattagg aaatacgtcc caagagttgc aatctcttca agtccagaat 420 ataaagcttg caggaagtct gcagcatgtg gctgaaaaac tctgtcgtga gctgtataac 480 aaagctggag gctatacaag aaacatggtg ccagcatctg cttcttctga gagcctcagg 540 cagcttccac acatggggga aagtgcagca gcacacaggt gcagcccttg tacagaacaa 600 tggaaatggc atggagacaa ttgctaccag ttctataaag acagcaaaag ttgggaggac 660 tgtaaatatt tctgccttag tgaaaactct accatgctga agataaacaa acaagaagac 720 ctggaatttg ccgcgtctca gagctactct gagtttttct actcttattg gacagggctt 780 ttgcgccctg acagtggcaa ggcctggctg tggatggatg gaaccccttt cacttctgaa 840 ctgttccata ttataataga tgtcaccagc ccaagaagca gagactgtgt ggccatcctt 900 aatgggatga tcttctcaaa ggactgcaaa gaattgaagc gttgtgtctg tgagagaagg 960 gcaggaatgg tgaagccaga gagcctccat gtcccccctg aaacattagg cgaaggtgac 1020 tgattcgccc tctgcaacta caaatagcag agtgagccag gcggtgccaa agcaagggct 1080 agttgagaca ttgggaaatg gaacataatc aggaaagact atctctctga ctagtacaaa 1140 atgggttctc gtgtttcctg ttcaggatca ccagcatttc tgagcttggg tttatgcacg 1200 tatttaacag tcacaagaag tcttatttac atgccaccaa ccaacctcag aaacccataa 1260 tgtcatctgc cttcttggct tagagataac ttttagctct ctttcttctc aatgtctaat 1320 atcacctccc tgttttcatg tcttccttac acttggtgga ataagaaact ttttgaagta 1380 gaggaaatac attgaggtaa catccttttc tctgacagtc aagtagtcca tcagaaattg 1440 gcagtcactt cccagattgt accagcaaat acacaaggaa ttctttttgt ttgtttcagt 1500 tcatactagt cccttcccaa tccatcagta aagaccccat ctgccttgtc catgccgttt 1560 cccaacaggg atgtcacttg atatgagaat ctcaaatctc aatgccttat aagcattcct 1620 tcctgtgtcc attaagactc tgataattgt ctcccctcca taggaatttc tcccaggaaa 1680 gaaatatatc cccatctccg tttcatatca gaactaccgt ccccgatatt cccttcagag 1740 agattaaaga ccagaaaaaa gtgagcctct tcatctgcac ctgtaatagt ttcagttcct 1800 attttcttcc attgacccat atttatacct ttcaggtact gaagatttaa taataataaa 1860 tgtaaatact gtgaagtgtg tgtgatttta caatggactt atggttggtg ggaaaattca 1920 gcatggaaat gcttttcaaa atatgatagc ggtcattatt ttgattgtgc cttactgaaa 1980 gtttttgggg aatttacaag agtactgatt acatgattat ctggagaaaa taagatgtct 2040 ttgaaataca tgttggcttc aagaaaacag ttttaacgtt ttcctaaaat gaaatctttt 2100 gaggtgagct tatggcatca acacatggtt gatgaggaag ctgagttgca ttagtgcaca 2160 tgatttccag tcaggtcatg ggaaatgaac agagacagtg acatctttgt agctgctcct 2220 ttgtgaggca cttctttctt gagatgactc catgcacaaa tataacaggg atcattggga 2280 atgacaccat cacagccacc aagnttattg ggttactgat aat 2323 <210> SEQ ID NO 37 <211> LENGTH: 307 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 37 Met Gln Ala Lys Tyr Ser Ser Thr Arg Asp Met Leu Asp Asp Asp Gly 1 5 10 15 Asp Thr Thr Met Ser Leu His Ser Gln Ala Ser Ala Thr Thr Arg His 20 25 30 Pro Glu Pro Arg Arg Thr Glu His Arg Ala Pro Ser Ser Thr Trp Arg 35 40 45 Pro Val Ala Leu Thr Leu Leu Thr Leu Cys Leu Val Leu Leu Ile Gly 50 55 60 Leu Ala Ala Leu Gly Leu Leu Phe Phe Gln Tyr Tyr Gln Leu Ser Asn 65 70 75 80 Thr Gly Gln Asp Thr Ile Ser Gln Met Glu Glu Arg Leu Gly Asn Thr 85 90 95 Ser Gln Glu Leu Gln Ser Leu Gln Val Gln Asn Ile Lys Leu Ala Gly 100 105 110 Ser Leu Gln His Val Ala Glu Lys Leu Cys Arg Glu Leu Tyr Asn Lys 115 120 125 Ala Gly Gly Tyr Thr Arg Asn Met Val Pro Ala Ser Ala Ser Ser Glu 130 135 140 Ser Leu Arg Gln Leu Pro His Met Gly Glu Ser Ala Ala Ala His Arg 145 150 155 160 Cys Ser Pro Cys Thr Glu Gln Trp Lys Trp His Gly Asp Asn Cys Tyr 165 170 175 Gln Phe Tyr Lys Asp Ser Lys Ser Trp Glu Asp Cys Lys Tyr Phe Cys 180 185 190 Leu Ser Glu Asn Ser Thr Met Leu Lys Ile Asn Lys Gln Glu Asp Leu 195 200 205 Glu Phe Ala Ala Ser Gln Ser Tyr Ser Glu Phe Phe Tyr Ser Tyr Trp 210 215 220 Thr Gly Leu Leu Arg Pro Asp Ser Gly Lys Ala Trp Leu Trp Met Asp 225 230 235 240 Gly Thr Pro Phe Thr Ser Glu Leu Phe His Ile Ile Ile Asp Val Thr 245 250 255 Ser Pro Arg Ser Arg Asp Cys Val Ala Ile Leu Asn Gly Met Ile Phe 260 265 270 Ser Lys Asp Cys Lys Glu Leu Lys Arg Cys Val Cys Glu Arg Arg Ala 275 280 285 Gly Met Val Lys Pro Glu Ser Leu His Val Pro Pro Glu Thr Leu Gly 290 295 300 Glu Gly Asp 305 <210> SEQ ID NO 38 <211> LENGTH: 2714 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 38 gaatcgagcc cgacgtcgca tgctcccggc cgccatggcc gcgggattcc cgggtcgacg 60 atttcgtcgg gaggaatgga aggagaaggc ggaatgtggg agggctcagg gggatgtggg 120 agggacgaac ggagaagggg gagagagggg ggtccagtct cccctggccg agcatttttt 180 ttttggaagt cctaggactg atctccagga ccagcactct tctcccagcc cttagggtcc 240 tgctcggcca aggccttccc tgccatgcga cctgtcagtg tctggcagtg gagcccctgg 300 gggctgctgc tgtgcctgct gtgcagttcg tgcttggggt ctccgtcccc ttccacgggc 360 cctgagaaga aggccgggag ccaggggctt cggttccggc tggctggctt ccccaggaag 420 ccctacgagg gccgcgtgga gatacagcga gctggtgaat ggggcaccat ctgcgatgat 480 gacttcacgc tgcaggctgc ccacatcctc tgccgggagc tgggcttcac agaggccaca 540 ggctggaccc acagtgccaa atatggccct ggaacaggcc gcatctggct ggacaacttg 600 agctgcagtg ggaccgagca gagtgtgact gaatgtgcct cccggggctg ggggaacagt 660 gactgtacgc acgatgagga tgctggggtc atctgcaaag accagcgcct ccctggcttc 720 tcggactcca atgtcattga ggtagagcat cacctgcaag tggaggaggt gcgaattcga 780 cccgccgttg ggtggggcag acgacccctg cccgtgacgg aggggctggt ggaagtcagg 840 cttcctgacg gctggtcgca agtgtgcgac aaaggctgga gcgcccacaa cagccacgtg 900 gtctgcggga tgctgggctt ccccagcgaa aagagggtca acgcggcctt ctacagaaag 960 ttgaggaagc gagcggccaa ggtctcagcc cgacacccca agccccttgg aaggctgcta 1020 gcccaacggc agcaacactc ctttggtctg catggggtgg cgtgcgtggg cacggaggcc 1080 cacctctccc tctgttccct ggagttctat cgtgccaatg acaccgccag gtgccctggg 1140 gggggccctg cagtggtgag ctgtgtgcca ggccctgtct acgcggcatc cagtggccag 1200 aagaagcaac aacagtcgaa gcctcagggg gaggcccgtg tccgtctaaa gggcggcgcc 1260 caccctggag agggccgggt agaagtcctg aaggccagca catggggcac agtctgtgac 1320 cgcaagtggg acctgcatgc agccagcgtg gtgtgtcggg agctgggctt cgggagtgct 1380 cgagaagctc tgagtggcgc tcgcatgggg cagggcatgg gtgctatcca cctgagtgaa 1440 gttcgctgct ctggacagga gctctccctc tggaagtgcc cccacaagaa catcacagct 1500 gaggattgtt cacatagcca ggatgccggg gtccggtgca acctacctta cactggggca 1560 gagaccagga tccgactcag tgggggccgc agccaacatg aggggcgagt cgaggtgcaa 1620 atagggggac ctgggcccct tcgctggggc ctcatctgtg gggatgactg ggggaccctg 1680 gaggccatgg tggcctgtag gcaactgggt ctgggctacg ccaaccacgg cctgcaggag 1740 acctggtact gggactctgg gaatataaca gaggtggtga tgagtggagt gcgctgcaca 1800 gggactgagc tgtccctgga tcagtgtgcc catcatggca cccacatcac ctgcaagagg 1860 acagggaccc gcttcactgc tggagtcatc tgttctgaga ctgcatcaga tctgttgctg 1920 cactcagcac tggtgcagga gaccgcctac atcgaagacc ggcccctgca tatgttgtac 1980 tgtgctgcgg aagagaactg cctggccagc tcagcccgct cagccaactg gccctatggt 2040 caccggcgtc tgctccgatt ctcctcccag atccacaacc tgggacgagc tgacttcagg 2100 cccaaggctg ggcgccactc ctgggtgtgg cacgagtgcc atgggcatta ccacagcatg 2160 gacatcttca ctcactatga tatcctcacc ccaaatggca ccaaggtggc tgagggccac 2220 aaagctagtt tctgtctcga agacactgag tgtcaggagg atgtctccaa gcggtatgag 2280 tgtgccaact ttggagagca aggcatcact gtgggttgct gggatctcta ccggcatgac 2340 attgactgtc agtggattga catcacggat gtgaagccag gaaactacat tctccaggtt 2400 gtcatcaacc caaactttga agtagcagag agtgacttta ccaacaatgc aatgaaatgt 2460 aactgcaaat atgatggaca tagaatctgg gtgcacaact gccacattgg tgatgccttc 2520 agtgaagagg cccacaggag gtttgaacgc tcccctggcc agaccagcac ctagattatg 2580 taagtgccac tgccctttgc aaaccgcccc tggcgcctaa tggcaggggt ctgaggctgc 2640 cattacctca ggagcttatc aagaaaccca tgtcagcaac catgtattgc ggccgctcta 2700 gaggaatcgc cagc 2714 <210> SEQ ID NO 39 <211> LENGTH: 769 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 39 Met Arg Pro Val Ser Val Trp Gln Trp Ser Pro Trp Gly Leu Leu Leu 1 5 10 15 Cys Leu Leu Cys Ser Ser Cys Leu Gly Ser Pro Ser Pro Ser Thr Gly 20 25 30 Pro Glu Lys Lys Ala Gly Ser Gln Gly Leu Arg Phe Arg Leu Ala Gly 35 40 45 Phe Pro Arg Lys Pro Tyr Glu Gly Arg Val Glu Ile Gln Arg Ala Gly 50 55 60 Glu Trp Gly Thr Ile Cys Asp Asp Asp Phe Thr Leu Gln Ala Ala His 65 70 75 80 Ile Leu Cys Arg Glu Leu Gly Phe Thr Glu Ala Thr Gly Trp Thr His 85 90 95 Ser Ala Lys Tyr Gly Pro Gly Thr Gly Arg Ile Trp Leu Asp Asn Leu 100 105 110 Ser Cys Ser Gly Thr Glu Gln Ser Val Thr Glu Cys Ala Ser Arg Gly 115 120 125 Trp Gly Asn Ser Asp Cys Thr His Asp Glu Asp Ala Gly Val Ile Cys 130 135 140 Lys Asp Gln Arg Leu Pro Gly Phe Ser Asp Ser Asn Val Ile Glu Val 145 150 155 160 Glu His His Leu Gln Val Glu Glu Val Arg Ile Arg Pro Ala Val Gly 165 170 175 Trp Gly Arg Arg Pro Leu Pro Val Thr Glu Gly Leu Val Glu Val Arg 180 185 190 Leu Pro Asp Gly Trp Ser Gln Val Cys Asp Lys Gly Trp Ser Ala His 195 200 205 Asn Ser His Val Val Cys Gly Met Leu Gly Phe Pro Ser Glu Lys Arg 210 215 220 Val Asn Ala Ala Phe Tyr Arg Lys Leu Arg Lys Arg Ala Ala Lys Val 225 230 235 240 Ser Ala Arg His Pro Lys Pro Leu Gly Arg Leu Leu Ala Gln Arg Gln 245 250 255 Gln His Ser Phe Gly Leu His Gly Val Ala Cys Val Gly Thr Glu Ala 260 265 270 His Leu Ser Leu Cys Ser Leu Glu Phe Tyr Arg Ala Asn Asp Thr Ala 275 280 285 Arg Cys Pro Gly Gly Gly Pro Ala Val Val Ser Cys Val Pro Gly Pro 290 295 300 Val Tyr Ala Ala Ser Ser Gly Gln Lys Lys Gln Gln Gln Ser Lys Pro 305 310 315 320 Gln Gly Glu Ala Arg Val Arg Leu Lys Gly Gly Ala His Pro Gly Glu 325 330 335 Gly Arg Val Glu Val Leu Lys Ala Ser Thr Trp Gly Thr Val Cys Asp 340 345 350 Arg Lys Trp Asp Leu His Ala Ala Ser Val Val Cys Arg Glu Leu Gly 355 360 365 Phe Gly Ser Ala Arg Glu Ala Leu Ser Gly Ala Arg Met Gly Gln Gly 370 375 380 Met Gly Ala Ile His Leu Ser Glu Val Arg Cys Ser Gly Gln Glu Leu 385 390 395 400 Ser Leu Trp Lys Cys Pro His Lys Asn Ile Thr Ala Glu Asp Cys Ser 405 410 415 His Ser Gln Asp Ala Gly Val Arg Cys Asn Leu Pro Tyr Thr Gly Ala 420 425 430 Glu Thr Arg Ile Arg Leu Ser Gly Gly Arg Ser Gln His Glu Gly Arg 435 440 445 Val Glu Val Gln Ile Gly Gly Pro Gly Pro Leu Arg Trp Gly Leu Ile 450 455 460 Cys Gly Asp Asp Trp Gly Thr Leu Glu Ala Met Val Ala Cys Arg Gln 465 470 475 480 Leu Gly Leu Gly Tyr Ala Asn His Gly Leu Gln Glu Thr Trp Tyr Trp 485 490 495 Asp Ser Gly Asn Ile Thr Glu Val Val Met Ser Gly Val Arg Cys Thr 500 505 510 Gly Thr Glu Leu Ser Leu Asp Gln Cys Ala His His Gly Thr His Ile 515 520 525 Thr Cys Lys Arg Thr Gly Thr Arg Phe Thr Ala Gly Val Ile Cys Ser 530 535 540 Glu Thr Ala Ser Asp Leu Leu Leu His Ser Ala Leu Val Gln Glu Thr 545 550 555 560 Ala Tyr Ile Glu Asp Arg Pro Leu His Met Leu Tyr Cys Ala Ala Glu 565 570 575 Glu Asn Cys Leu Ala Ser Ser Ala Arg Ser Ala Asn Trp Pro Tyr Gly 580 585 590 His Arg Arg Leu Leu Arg Phe Ser Ser Gln Ile His Asn Leu Gly Arg 595 600 605 Ala Asp Phe Arg Pro Lys Ala Gly Arg His Ser Trp Val Trp His Glu 610 615 620 Cys His Gly His Tyr His Ser Met Asp Ile Phe Thr His Tyr Asp Ile 625 630 635 640 Leu Thr Pro Asn Gly Thr Lys Val Ala Glu Gly His Lys Ala Ser Phe 645 650 655 Cys Leu Glu Asp Thr Glu Cys Gln Glu Asp Val Ser Lys Arg Tyr Glu 660 665 670 Cys Ala Asn Phe Gly Glu Gln Gly Ile Thr Val Gly Cys Trp Asp Leu 675 680 685 Tyr Arg His Asp Ile Asp Cys Gln Trp Ile Asp Ile Thr Asp Val Lys 690 695 700 Pro Gly Asn Tyr Ile Leu Gln Val Val Ile Asn Pro Asn Phe Glu Val 705 710 715 720 Ala Glu Ser Asp Phe Thr Asn Asn Ala Met Lys Cys Asn Cys Lys Tyr 725 730 735 Asp Gly His Arg Ile Trp Val His Asn Cys His Ile Gly Asp Ala Phe 740 745 750 Ser Glu Glu Ala His Arg Arg Phe Glu Arg Ser Pro Gly Gln Thr Ser 755 760 765 Thr <210> SEQ ID NO 40 <211> LENGTH: 1877 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 40 gtaggcactg tgcaaaacat actagtggat atagagatga ataagaaaaa gcccctgcac 60 tcaaagagct ctcggattca tcaacaaatt attgtgcagt tagatagcct ccctccacct 120 gtcttctcag agcaggtaat ggcaagcatg gctgccgtgc tcacctgggc tctggctctt 180 ctttcagcgt tttcggccac ccaggcacgg aaaggcttct gggactactt cagccagacc 240 agcggggaca aaggcagggt ggagcagatc catcagcaga agatggctcg cgagcccgcg 300 accctgaaag acagccttga gcaagacctc aacaatatga acaagttcct ggaaaagctg 360 aggcctctga gtgggagcga ggctcctcgg ctcccacagg acccggtggg catgcggcgg 420 cagctgcagg aggagttgga ggaggtgaag gctcgcctcc agccctacat ggcagaggcg 480 cacgagctgg tgggctggaa tttggagggc ttgcggcagc aactgaagcc ctacacgatg 540 gatctgatgg agcaggtggc cctgcgcgtg caggagctgc aggagcagtt gcgcgtggtg 600 ggggaagaca ccaaggccca gttgctgggg ggcgtggacg aggcttgggc tttgctgcag 660 ggactgcaga gccgcgtggt gcaccacacc ggccgcttca aagagctctt ccacccatac 720 gccgagagcc tggtgagcgg catcgggcgc cacgtgcagg agctgcaccg cagtgtggct 780 ccgcacgccc ccgccagccc cgcgcgcctc agtcgctgcg tgcaggtgct ctcccggaag 840 ctcacgctca aggccaaggc cctgcacgca cgcatccagc agaacctgga ccagctgcgc 900 gaagagctca gcagagcctt tgcaggcact gggactgagg aaggggccgg cccggacccc 960 cagatgctct ccgaggaggt gcgccagcga cttcaggctt tccgccagga cacctacctg 1020 cagatagctg ccttcactcg cgccatcgac caggagactg aggaggtcca gcagcagctg 1080 gcgccacctc caccaggcca cagtgccttc gccccagagt ttcaacaaac agacagtggc 1140 aaggttctga gcaagctgca ggcccgtctg gatgacctgt gggaagacat cactcacagc 1200 cttcatgacc agggccacag ccatctgggg gacccctgag gatctacctg cccaggccca 1260 ttcccagctc cttgtctggg gagccttggc tctgagcctc tagcatggtt cagtccttga 1320 aagtggcctg ttgggtggag ggtggaaggt cctgtgcagg acagggaggc caccaaaggg 1380 gctgctgtct cctgcacatc cagcctcctg cgactcccca atctggatgc attacattca 1440 ccaggctttg caaacccagc ctcccagtgc tcatttggga atgctcatga gttactccat 1500 tcaagggtga gggagtaggg agggagaggc accatgcatg tgggtgatta tctgcaagcc 1560 tgtttgccgt gatgctggaa gcctgtgcca ctacatcctg gagtctgaca ctgagcccct 1620 gcgagtgacc gtgagcacac agttccgtag cggggcccat acgagactcg acgcgcgcgc 1680 accacgaggt cccgagggag gacactcgac ggacacgagt gacgggaaat gtgcatctac 1740 actagcgcgc gacagctaga gcgatgacgg cgaggacgtc tcgcagccta ccagcaacgc 1800 gaagacgtgc ctcccggcgt cgtatggatt aacaagctcc aagtagggtg tacaacgccg 1860 cagcatgaac tcccagg 1877 <210> SEQ ID NO 41 <211> LENGTH: 400 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 41 Met Asn Lys Lys Lys Pro Leu His Ser Lys Ser Ser Arg Ile His Gln 1 5 10 15 Gln Ile Ile Val Gln Leu Asp Ser Leu Pro Pro Pro Val Phe Ser Glu 20 25 30 Gln Val Met Ala Ser Met Ala Ala Val Leu Thr Trp Ala Leu Ala Leu 35 40 45 Leu Ser Ala Phe Ser Ala Thr Gln Ala Arg Lys Gly Phe Trp Asp Tyr 50 55 60 Phe Ser Gln Thr Ser Gly Asp Lys Gly Arg Val Glu Gln Ile His Gln 65 70 75 80 Gln Lys Met Ala Arg Glu Pro Ala Thr Leu Lys Asp Ser Leu Glu Gln 85 90 95 Asp Leu Asn Asn Met Asn Lys Phe Leu Glu Lys Leu Arg Pro Leu Ser 100 105 110 Gly Ser Glu Ala Pro Arg Leu Pro Gln Asp Pro Val Gly Met Arg Arg 115 120 125 Gln Leu Gln Glu Glu Leu Glu Glu Val Lys Ala Arg Leu Gln Pro Tyr 130 135 140 Met Ala Glu Ala His Glu Leu Val Gly Trp Asn Leu Glu Gly Leu Arg 145 150 155 160 Gln Gln Leu Lys Pro Tyr Thr Met Asp Leu Met Glu Gln Val Ala Leu 165 170 175 Arg Val Gln Glu Leu Gln Glu Gln Leu Arg Val Val Gly Glu Asp Thr 180 185 190 Lys Ala Gln Leu Leu Gly Gly Val Asp Glu Ala Trp Ala Leu Leu Gln 195 200 205 Gly Leu Gln Ser Arg Val Val His His Thr Gly Arg Phe Lys Glu Leu 210 215 220 Phe His Pro Tyr Ala Glu Ser Leu Val Ser Gly Ile Gly Arg His Val 225 230 235 240 Gln Glu Leu His Arg Ser Val Ala Pro His Ala Pro Ala Ser Pro Ala 245 250 255 Arg Leu Ser Arg Cys Val Gln Val Leu Ser Arg Lys Leu Thr Leu Lys 260 265 270 Ala Lys Ala Leu His Ala Arg Ile Gln Gln Asn Leu Asp Gln Leu Arg 275 280 285 Glu Glu Leu Ser Arg Ala Phe Ala Gly Thr Gly Thr Glu Glu Gly Ala 290 295 300 Gly Pro Asp Pro Gln Met Leu Ser Glu Glu Val Arg Gln Arg Leu Gln 305 310 315 320 Ala Phe Arg Gln Asp Thr Tyr Leu Gln Ile Ala Ala Phe Thr Arg Ala 325 330 335 Ile Asp Gln Glu Thr Glu Glu Val Gln Gln Gln Leu Ala Pro Pro Pro 340 345 350 Pro Gly His Ser Ala Phe Ala Pro Glu Phe Gln Gln Thr Asp Ser Gly 355 360 365 Lys Val Leu Ser Lys Leu Gln Ala Arg Leu Asp Asp Leu Trp Glu Asp 370 375 380 Ile Thr His Ser Leu His Asp Gln Gly His Ser His Leu Gly Asp Pro 385 390 395 400 <210> SEQ ID NO 42 <211> LENGTH: 2128 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 42 gcaccggtcc ggaattcccg ggtcgacgat ttcgtctcaa cattcagcag aggccccaga 60 tcagcgtctg agccaggcca acaatgacca aggaggatgg gatcctgggt gcagctcatc 120 acaagcgtcg gggtgcagca aaaccatcca ggctggacag tggctggaca gttccaagaa 180 aagaaacgct tcactgaaga agtcattgaa tacttccaga agaaagttag cccagtgcat 240 ctgaaaatcc tgctgactag cgatgaagcc tggaagagat ttgtgcgtgt ggctgaattg 300 cccagggaag aggcagatgc tctctatgaa gctctgaaga atcttacacc atatgtgact 360 attgaggaca aagacatgca gcaaaaagaa cagcagttta gggagtggtt tttgaaagag 420 tttcctcaaa tcagatggaa gattcaggag tccatagaaa ggcttcgtgt cattgcaaat 480 gagattgaaa aggtccacag aggctgcgtc atcgccaatg tggtgtctgg ctccactggc 540 atcctgtctg tcattggcgt tatgttggca ccatttacag cagggctgag cctgagcatt 600 actgcagctg gggtagggct gggaatagca tctgccacgg ctgggatcgc ctccagcatc 660 gtggagaaca catacacaag gtcagcagaa ctcacagcca gcaggctgac tgcaaccagc 720 actgaccaat tggaggcatt aagggacatt ctgcatgaca tcacacccaa tgtgctttcc 780 tttgcacttg attttgacga agccacaaaa atgattgcga atgatgtcca tacactcagg 840 agatctaaag ccactgttgg acgccctttg attgcttggc gatatgtacc tataaatgtt 900 gttgagacac tgagaacacg tggggccccc acccggatag tgagaaaagt agcccggaac 960 ctgggcaagg ccacttcagg tgtccttgtt gtgctggatg tagtcaacct tgtgcaagac 1020 tcactggact tgcacaaggg ggcaaaatcc gagtctgctg agtcgctgag gcagtgggct 1080 caggagctgg aggagaatct caatgagctc acccatatcc atcagagtct aaaagcaggc 1140 taggcccaat tgttgcggga agtcagggac cccaaacgga gggactggct gaagccatgg 1200 cagaagaacg tggattgtga agatttcatg gacatttatt agttccccaa attaatactt 1260 ttataatttc ctatgcctgt ctttaccgca atctctaaac acaaattgtg aagatttcat 1320 ggacacttat cacttcccca atcaataccc ttgtgatttc ttatgcctgt ctttacttta 1380 atctcctaat cctgtcagct gaggaggatg tatgtcacct caggaccatg tgataattgc 1440 gttaactgca caaattgtag agcatgtgtg tttgaacaat atgaaatctg ggcaccttga 1500 aaaaagaaca ggataacagc aattgttcag ggaataagag agataacctt aaactctgac 1560 caacagtgag ccgggtggaa cagagtcata tttctcttct ttcaaaagca aatgggagaa 1620 atatcgctga attctttttc tcagcaagga acatccctga gaaagagaat gcacccctga 1680 gggtgggtct ataaatggcc tccttgggtg tggccatctt ctatggtcga gactgtaggg 1740 atgaaataaa ccccagtctc ccatagtgct cccaggctta ttaggaagag gaaattcccg 1800 cctaataaat tttggtcaga ccggttgctc tcaaaaccct gtctcctgat aagatgttat 1860 caatgacaat ggtgcctgaa acctcattag caattttaat ttctccccgg tcctgtggtc 1920 ctgtgatctc accctgcctc cacttgcctt gtgatattct attaccttgt gaagtaggtg 1980 atctttgtga cccacaccct attcatacac tccctcccct tttgaaagtc cctaataaaa 2040 acttgctggt tttgcagctt gtgaggcatc acggaaccta ctgatgtgtg atgtctcccc 2100 tggacaccta gctttaaaat ttcaaaaa 2128 <210> SEQ ID NO 43 <211> LENGTH: 348 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 43 Met Gly Ser Trp Val Gln Leu Ile Thr Ser Val Gly Val Gln Gln Asn 1 5 10 15 His Pro Gly Trp Thr Val Ala Gly Gln Phe Gln Glu Lys Lys Arg Phe 20 25 30 Thr Glu Glu Val Ile Glu Tyr Phe Gln Lys Lys Val Ser Pro Val His 35 40 45 Leu Lys Ile Leu Leu Thr Ser Asp Glu Ala Trp Lys Arg Phe Val Arg 50 55 60 Val Ala Glu Leu Pro Arg Glu Glu Ala Asp Ala Leu Tyr Glu Ala Leu 65 70 75 80 Lys Asn Leu Thr Pro Tyr Val Thr Ile Glu Asp Lys Asp Met Gln Gln 85 90 95 Lys Glu Gln Gln Phe Arg Glu Trp Phe Leu Lys Glu Phe Pro Gln Ile 100 105 110 Arg Trp Lys Ile Gln Glu Ser Ile Glu Arg Leu Arg Val Ile Ala Asn 115 120 125 Glu Ile Glu Lys Val His Arg Gly Cys Val Ile Ala Asn Val Val Ser 130 135 140 Gly Ser Thr Gly Ile Leu Ser Val Ile Gly Val Met Leu Ala Pro Phe 145 150 155 160 Thr Ala Gly Leu Ser Leu Ser Ile Thr Ala Ala Gly Val Gly Leu Gly 165 170 175 Ile Ala Ser Ala Thr Ala Gly Ile Ala Ser Ser Ile Val Glu Asn Thr 180 185 190 Tyr Thr Arg Ser Ala Glu Leu Thr Ala Ser Arg Leu Thr Ala Thr Ser 195 200 205 Thr Asp Gln Leu Glu Ala Leu Arg Asp Ile Leu His Asp Ile Thr Pro 210 215 220 Asn Val Leu Ser Phe Ala Leu Asp Phe Asp Glu Ala Thr Lys Met Ile 225 230 235 240 Ala Asn Asp Val His Thr Leu Arg Arg Ser Lys Ala Thr Val Gly Arg 245 250 255 Pro Leu Ile Ala Trp Arg Tyr Val Pro Ile Asn Val Val Glu Thr Leu 260 265 270 Arg Thr Arg Gly Ala Pro Thr Arg Ile Val Arg Lys Val Ala Arg Asn 275 280 285 Leu Gly Lys Ala Thr Ser Gly Val Leu Val Val Leu Asp Val Val Asn 290 295 300 Leu Val Gln Asp Ser Leu Asp Leu His Lys Gly Ala Lys Ser Glu Ser 305 310 315 320 Ala Glu Ser Leu Arg Gln Trp Ala Gln Glu Leu Glu Glu Asn Leu Asn 325 330 335 Glu Leu Thr His Ile His Gln Ser Leu Lys Ala Gly 340 345 <210> SEQ ID NO 44 <211> LENGTH: 988 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (129)..(971) <221> NAME/KEY: misc_feature <222> LOCATION: (12) <223> OTHER INFORMATION: n = a, c, g, or t <221> NAME/KEY: misc_feature <222> LOCATION: (14) <223> OTHER INFORMATION: n = a, c, g, or t <221> NAME/KEY: misc_feature <222> LOCATION: (15) <223> OTHER INFORMATION: n = a, c, g, or t <221> NAME/KEY: misc_feature <222> LOCATION: (16) <223> OTHER INFORMATION: n = a, c, g, or t <221> NAME/KEY: misc_feature <222> LOCATION: (17) <223> OTHER INFORMATION: n = a, c, g, or t <221> NAME/KEY: misc_feature <222> LOCATION: (41) <223> OTHER INFORMATION: n = a, c, g, or t <221> NAME/KEY: misc_feature <222> LOCATION: (42) <223> OTHER INFORMATION: n = a, c, g, or t <400> SEQUENCE: 44 agagctgccg gngnnnnaat ggatagaata ctcttgacca nngacgcacg agcctgaact 60 agctcacagt agcccggcgg cccagggcaa tccgaccaca tttcactctc accgctgtag 120 gaatccag atg cag gcc aag tac agc agc acg agg gac atg ctg gat gat 170 Met Gln Ala Lys Tyr Ser Ser Thr Arg Asp Met Leu Asp Asp 1 5 10 gat ggg gac acc acc atg agc ctg cat tct caa gcc tct gcc aca act 218 Asp Gly Asp Thr Thr Met Ser Leu His Ser Gln Ala Ser Ala Thr Thr 15 20 25 30 cgg cat cca gag ccc cgg cgc aca gtt ttt cag tac tac cag ctc tcc 266 Arg His Pro Glu Pro Arg Arg Thr Val Phe Gln Tyr Tyr Gln Leu Ser 35 40 45 aat act ggt caa gac acc att tct caa atg gaa gaa aga tta gga aat 314 Asn Thr Gly Gln Asp Thr Ile Ser Gln Met Glu Glu Arg Leu Gly Asn 50 55 60 acg tcc caa gag ttg caa tct ctt caa gtc cag aat ata aag ctt gca 362 Thr Ser Gln Glu Leu Gln Ser Leu Gln Val Gln Asn Ile Lys Leu Ala 65 70 75 gga agt ctg cag cat gtg gct gaa aaa ctc tgt cgt gag ctg tat aac 410 Gly Ser Leu Gln His Val Ala Glu Lys Leu Cys Arg Glu Leu Tyr Asn 80 85 90 aaa gct gga ggc tat aca aga aac atg gtg cca gca tct gct tct tct 458 Lys Ala Gly Gly Tyr Thr Arg Asn Met Val Pro Ala Ser Ala Ser Ser 95 100 105 110 gag agc ctc agg cag ctt cca cac atg ggg gaa agt gca gca gca cac 506 Glu Ser Leu Arg Gln Leu Pro His Met Gly Glu Ser Ala Ala Ala His 115 120 125 agg tgc agc cct tgt aca gaa caa tgg aaa tgg cat gga gac aat tgc 554 Arg Cys Ser Pro Cys Thr Glu Gln Trp Lys Trp His Gly Asp Asn Cys 130 135 140 tac cag ttc tat aaa gac agc aaa agt tgg gag gac tgt aaa tat ttc 602 Tyr Gln Phe Tyr Lys Asp Ser Lys Ser Trp Glu Asp Cys Lys Tyr Phe 145 150 155 tgc ctt agt gaa aac tct acc atg ctg aag ata aac aaa caa gaa gac 650 Cys Leu Ser Glu Asn Ser Thr Met Leu Lys Ile Asn Lys Gln Glu Asp 160 165 170 ctg gaa ttt gcc gcg tct cag agc tac tct gag ttt ttc tac tct tat 698 Leu Glu Phe Ala Ala Ser Gln Ser Tyr Ser Glu Phe Phe Tyr Ser Tyr 175 180 185 190 tgg aca ggg ctt ttg cgc cct gac agt ggc aag gcc tgg ctg tgg atg 746 Trp Thr Gly Leu Leu Arg Pro Asp Ser Gly Lys Ala Trp Leu Trp Met 195 200 205 gat gga acc cct ttc act tct gaa ctg ttc cat att ata ata gat gtc 794 Asp Gly Thr Pro Phe Thr Ser Glu Leu Phe His Ile Ile Ile Asp Val 210 215 220 acc agc cca aga agc aga gac tgt gtg gcc atc ctt aat ggg atg atc 842 Thr Ser Pro Arg Ser Arg Asp Cys Val Ala Ile Leu Asn Gly Met Ile 225 230 235 ttc tca aag gac tgc aaa gaa ttg aag cgt tgt gtc tgt gag aga agg 890 Phe Ser Lys Asp Cys Lys Glu Leu Lys Arg Cys Val Cys Glu Arg Arg 240 245 250 gca gga atg gtg aag cca gag agc ctc cat gtc ccc cct gaa aca tta 938 Ala Gly Met Val Lys Pro Glu Ser Leu His Val Pro Pro Glu Thr Leu 255 260 265 270 ggc gaa ggt gac atg cat cat cat cat cat cat tagcctaggt tctagac 988 Gly Glu Gly Asp Met His His His His His His 275 280 <210> SEQ ID NO 45 <211> LENGTH: 281 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 45 Met Gln Ala Lys Tyr Ser Ser Thr Arg Asp Met Leu Asp Asp Asp Gly 1 5 10 15 Asp Thr Thr Met Ser Leu His Ser Gln Ala Ser Ala Thr Thr Arg His 20 25 30 Pro Glu Pro Arg Arg Thr Val Phe Gln Tyr Tyr Gln Leu Ser Asn Thr 35 40 45 Gly Gln Asp Thr Ile Ser Gln Met Glu Glu Arg Leu Gly Asn Thr Ser 50 55 60 Gln Glu Leu Gln Ser Leu Gln Val Gln Asn Ile Lys Leu Ala Gly Ser 65 70 75 80 Leu Gln His Val Ala Glu Lys Leu Cys Arg Glu Leu Tyr Asn Lys Ala 85 90 95 Gly Gly Tyr Thr Arg Asn Met Val Pro Ala Ser Ala Ser Ser Glu Ser 100 105 110 Leu Arg Gln Leu Pro His Met Gly Glu Ser Ala Ala Ala His Arg Cys 115 120 125 Ser Pro Cys Thr Glu Gln Trp Lys Trp His Gly Asp Asn Cys Tyr Gln 130 135 140 Phe Tyr Lys Asp Ser Lys Ser Trp Glu Asp Cys Lys Tyr Phe Cys Leu 145 150 155 160 Ser Glu Asn Ser Thr Met Leu Lys Ile Asn Lys Gln Glu Asp Leu Glu 165 170 175 Phe Ala Ala Ser Gln Ser Tyr Ser Glu Phe Phe Tyr Ser Tyr Trp Thr 180 185 190 Gly Leu Leu Arg Pro Asp Ser Gly Lys Ala Trp Leu Trp Met Asp Gly 195 200 205 Thr Pro Phe Thr Ser Glu Leu Phe His Ile Ile Ile Asp Val Thr Ser 210 215 220 Pro Arg Ser Arg Asp Cys Val Ala Ile Leu Asn Gly Met Ile Phe Ser 225 230 235 240 Lys Asp Cys Lys Glu Leu Lys Arg Cys Val Cys Glu Arg Arg Ala Gly 245 250 255 Met Val Lys Pro Glu Ser Leu His Val Pro Pro Glu Thr Leu Gly Glu 260 265 270 Gly Asp Met His His His His His His 275 280 

What is claimed is:
 1. An isolated polynucleotide comprising a polynucleotide selected from the group consisting of: (a) a poiynucleotide having the nucleotide sequence of SEQ ID NO: 1, 3, 5, 7, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42 or 44; (b) a polynucleotide having the protein coding nucleotide sequence of a polynucleotide of (a); and (c) a polynucleotide having the mature protein coding nucleotide sequence of a polynucleotide of (a).
 2. An isolated polynucleotide encoding a polypeptide with biological activity, comprising a polynucleotide that encodes the amino acid sequence of SEQ ID NO: 2, 4, 6, 8, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43 or45 or the mature protein sequence thereof.
 3. An isolated polynucleotide encoding a polypeptide with biological activity that hybridizes under highly stringent conditions to the complement of a polynucleotide of any one of claims 1 or
 2. 4. An isolated polynucleotide encoding a polypeptide with biological activity, said polynucleotide having greater than about 90% sequence identity with the polynucleotide of claim 1 or
 2. 5. The polynucleotide of claim 1 or 2 which is a DNA.
 6. An isolated polynucleotide which comprises a complement of the polynucleotide of claim
 1. 7. An expression vector comprising the DNA of claim
 5. 8. A host cell genetically engineered to express the DNA of claim
 5. 9. A host cell genetically engineered to contain the DNA of claim 5 in operative association with a regulatory sequence that controls expression of the DNA in the host cell.
 10. An isolated polypeptide with biological activity comprising the amino acid sequence of SEQ ID NO: 2, 4, 6, 8, 11, 13, 15, 17, 19, 21, 23, 25 27, 29, 31, 33, 35, 37, 39, 41, 43 or 45 or the mature protein sequence thereof.
 11. An isolated polypeptide with biological activity selected from the group consisting of: a) a polypeptide having greater than about 90% sequence identity with the polypeptide of claim 10, and b) a polypeptide encoded by the polynucleotide of claim
 3. 12. A composition comprising the polypeptide of claim 10 or 11 and a carrier.
 13. An antibody directed against the polypeptide of claim 10 or
 11. 14. A method for detecting a polynucleotide of claim 3 in a sample, comprising the steps of: a) contacting the sample with a compound that binds to and forms a complex with the polynucleotide for a period sufficient to form the complex; and b) detecting the complex, so that if a complex is detected, a polynucleotide of claim 3 is detected.
 15. A method for detecting a polynucleotide of claim 3 in a sample, comprising the steps of: a) contacting the sample under stringent hybridization conditions with nucleic acid primers that anneal to a polynucleotide of claim 3 under such conditions; and b) amplifying the polynucleotides of claim 3 so that if a polynucleotide is amplified, a polynucleotide of claim 3 is detected.
 16. The method of claim 15, wherein the polynucleotide is an RNA molecule that encodes a polypeptide of claim 11, and the method further comprises reverse transcribing an annealed RNA molecule into a cDNA polynucleotide.
 17. A method for detecting a polypeptide of claim 11 in a sample, comprising: a) contacting the sample with a compound that binds to and forms a complex with the polypeptide for a period sufficient to form the complex; and b) detecting the complex, so that if a complex is detected, a polypeptide of claim 11 is detected.
 18. A method for identifying a compound that binds to a polypeptide of claim 11, comprising: a) contacting a compound with a polypeptide of claim 11 for a time sufficient to form a polypeptide/compound complex; and b) detecting the complex, so that if a polypeptide/compound complex is detected, a compound that binds to a polypeptide of claim 11 is identified.
 19. A method for identifying a compound that binds to a polypeptide of claim 11 comprising: a) contacting a compound with a polypeptide of claim 11, in a cell, for a time sufficient to form a polypeptide/compound complex, wherein the complex drives expression of a reporter gene sequence in the cell; and b) detecting the complex by detecting reporter gene sequence expression, so that if a polypeptide/compound complex is detected, a compound that binds to a polypeptide of claim 11 is identified.
 20. A method of producing the polypeptide of claim 11, comprising, a) culturing the host cell of claim 8 for a period of time sufficient to express the polypeptide; and b) isolating the polypeptide from the cell or culture media in which the cell is grown. 